Nrneph.2014.170

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1
Vascular Medicine
Institute (N.M.R., J.S.I.),
Thomas E. Starzl
Transplantation
Institute (N.M.R., J.S.I.,
A.W.T.), University of
Pittsburgh School
of Medicine, W1544
Biomedical Science
Tower, 200 Lothrop
Street, Pittsburgh,
PA 15261, USA. MRC
Centre for Inflammation
Research, Queen’s
Medical Research
Institute, University
of Edinburgh, 47 Little
France Crescent,
Edinburgh EH16 4TJ,
UK (D.A.F., J.H.).
Correspondence to:
A.W.T.
thomsonaw@upmc.edu
Dendritic cells and macrophages in the
kidney: a spectrum of good and evil
Natasha M. Rogers, David A. Ferenbach, Jeffrey S. Isenberg,Angus W.Thomson and Jeremy Hughes
Abstract | Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous
network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and
regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection.
Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of
renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the
aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction
of these cell types is complex and incompletely understood, and the same is true of their interplay and
relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss
the common and distinct characteristics of DCs and macrophages, as well as key advances that have
identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles
in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority
for further investigation, and highlight the prospects for translational and therapeutic application of the
knowledge acquired.
Rogers, N. M. et al. Nat. Rev. Nephrol. advance online publication 30 September 2014; doi:10.1038/nrneph.2014.170
Introduction
The manifestations of kidney disease are protean and
include acute kidney injury (AKI) due to ischaemia–
reperfusion or direct tubular cytotoxicity; autoimmune
glomerulonephritis; and rejection of kidney transplants
through mechanisms that affect the glomerular, inter-
stitial and vascular compartments. Increasing molec-
ular evidence now demonstrates the pivotal role of
nonparenchymal cells in determining both renal tissue
injury and subsequent reparative responses following
diverse insults. In particular, advances in technology
and the understanding of innate and adaptive immuno-
pathological cellular responses have facilitated identifica-
tion of dendritic cells (DCs) and macrophages, as well
as assessment of their function, in nonlymphoid solid
organs such as the kidney. Both of these cell types reside
within the renal interstitium, and possess the capacity
to activate and regulate both protective and deleterious
renal pathology. DCs have long been established as indis-
pensable antigen-presenting cells (APCs), which act as
systemic sentinels capable of responding to endogenous
and exogenous ‘danger’ signals to initiate and propagate
immune responses to inciting antigens or induce immune
tolerance.1–3
Macrophages have been defined as a distinct,
but related population of APCs (albeit less potent than
DCs), whose primary functions are maintenance of tissue
homeostasis and phagocytic clearance of various native
and foreign bodies.
In this Review, we examine the archetypal components
of the nonparenchymal compartment in the kidney. We
consider the advances that have been made in understand-
ing the discrete but overlapping roles of both DCs and
macrophages—a difficult task owing to the substantial
functional and phenotypic similarity between these mono-
nuclear phagocyte populations (Figure 1). We also discuss
how innovations, such as the identification and assessment
of distinct lineage markers and gene expression profiles,
transgenic mouse models and cell ablation techniques,
have facilitated the discrimination of DC and macro
phage subsets that function in tissue homeostasis and
immune tolerance, acute and chronic inflammationand
alloimmunity. We note, however, that considerable limi-
tations remain for many of these approaches, particu-
larly related to the ability to accurately target DCs and/
or macrophages to modulate disease outcome, in addi-
tion to questions regarding their relevance to human
kidney disease.
Defining DCs and macrophages
Considerable flexibility, heterogeneity and complexity is
recognized within the myeloid–monocyte developmental
lineage.4
Forexample,bothDCsandmacrophagesoriginate
from common progenitor cells in the bone marrow under
the influence of key growth factors (Figure 2): colony-
stimulating factor 1 (CSF‑1; also known as macrophage
colony-stimulatingfactor[M‑CSF]),fms‑likerelatedtyros-
inekinase3ligand(FLT3LG),andgranulocyte-macrophage
Competing interests
J.S.I. is Chair of the Scientific Advisory Boards of Radiation
Control Technologies and Vasculox. A.W.T. is co-inventor of
a US patent (6,224,859 B1) for the generation of tolerogenic
dendritic cells to promote transplant tolerance. The other
authors declare no competing interests.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

2 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph
colony-stimulating factor (GM‑CSF).5–7
Furthermore,
monocytes recruited from the circulation can differenti-
ate into tissue macrophages or inflammatory DCs during
disease processes.8,9
Thus, how best to define DC versus
macrophage cell types and activities (Figure 1) has been
Key points
■■ Dendritic cells (DCs) and macrophages are distinct cell types, but demonstrate
similarities in terms of ontogeny, phenotype, and function
■■ Both of these cell types are present within the renal interstitium and are critical
to homeostatic regulation of the kidney environment
■■ The numbers of DCs and macrophages in the kidney increase following renal injury
■■ A variety of DC and macrophage subtypes exist, each with distinct phenotypes
and activities, and many can be identified based on panels of cellular markers
■■ The manifestation of glomerular or tubular kidney disease, as well as disease
outcome in preclinical models, is determined by the subtype of DC and/or
macrophage involved
■■ A number of pharmacological or genetic approaches are available to deplete
or eliminate DCs or macrophages in preclinical models, but the effects of such
interventions are not renal-specific
an important area of contention, and this issue remains
controversial (Box 1).10–13
Currently, no definitive cel-
lular demarcation has been established, and studies have
tended to investigate either DCs or macrophages, with
segregation based on traditional interpretations of identi-
fication. Specifically, such research efforts—predominantly
in mouse models—have relied on the supposition that
macrophages or DCs can be accurately identified accord-
ing to expression levels of the ‘macrophage’ markers F4/80
(also known as EGF-like module-containing mucin-like
hormone receptor-like 1 [EMR1]) and CD11b (integrin
αM
) or the ‘DC marker’ CD11c (integrin αx
). However,
these markers are not exclusive to their respective cell
types (Figure 1); bone-marrow-derived macrophages can
express CD11c in vitro, whereas DCs can express F4/80
and CD11b, suggesting that these markers do not identify
unique cell populations.14,15
The incomplete restriction
of such cell-surface markers to specific cell types compli-
cates the interpretation of experimental data based on this
method of cell identification. In addition, this limitation
Functions
Tissue surveillance
Source of chemokines and cytokines
Phagocytosis of debris and pathogens
Cytotoxicity
Fibrosis and remodelling of ECM
Markers of inflammatory
M1 macrophages
Markers of
anti-inflammatory
M2 macrophages
CSF-1R (CD115)
CD14
CD62L
Ly6G
(Gr-1)
Ly6C
CD86
(B7.2)
MHC II
CD11b
(integrin αX
)
F4/80
(EMR1)CD11b
(integrin αM
)
CD80
(B7.1)
IL-4R/
IL-10R
CD206
CD163
CD68
FcγRII (CD32)
*ICAM-1 (CD54)
FcγRIII (CD16)
SIRPα
DC-SIGN
(CD209)*
BDCA-1 (CD1c)*
FLT3 (CD135)
CX3CR1
CD103 (integrin αE
)
CCR7 (maturation)
Macrophage
Shared antigens
Dendritic cell
ID-2, IRF8,
ZBTB46,
B-ATF-3
IRF5
IRF4
STAT3
Functions
Tissue surveillance
Source of chemokines and cytokines
Phagocytosis
Antigen presentation and T-cell stimulation
Induction of immune toleranceIL-6, IL-10, IL-12,TNF, TGF-β
Figure 1 | The heterogeneous but overlapping phenotype and functions of renal DCs and macrophages. DCs are traditionally
described as mediators of immune surveillance and antigen presentation, and as the primary determinants of responses to
antigens—through initiation of either immune effector-cell functions or the development of tolerance. Macrophages also
function as innate immune cells, predominantly through phagocytosis and production of toxic metabolites. However, the
classical paradigm of DC versus macrophage phenotypes and functions is increasingly indistinct within the kidney, as these
cells exhibit overlapping surface markers, functional capabilities, and ontogenic pathways. This molecular and phenotypic
overlap between cell types and subsets complicates their identification and evaluation. *Marker described only in humans.
Abbreviations: B‑ATF‑3, basic leucine zipper transcription factor ATF-like 3; BDCA‑1, blood dendritic cell antigen 1; CCR, CC
chemokine receptor; CSF-1R, colony-stimulating factor 1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell;
DC‑SIGN, dendritic-cell-specific ICAM‑3-grabbing non-integrin; ECM, extracellular matrix; EMR1, EGF-like module-containing
mucin-like hormone receptor-like 1; FcγR(II/III), low affinity IgG Fc region receptor (II/III); FLT3, fms-like tyrosine kinase 3; Gr‑1,
granulocyte-differentiation antigen‑1; ICAM‑1, intercellular adhesion molecule 1; ID‑2, inhibitor of DNA binding 2; IL‑4R, IL‑4
receptor; IL‑10R, IL‑10 receptor; IRF, interferon regulatory factor; Ly6(C/G), lymphocyte antigen 6(C/G); SIRPα, signal-regulatory
protein α (also known as tyrosine-protein phosphatase nonreceptor type substrate 1); STAT3, signal transducer and activator
of transcription 3; ZBTB46, zinc finger and BTB domain containing protein 46.
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should be considered when interpreting studies involving
conditional cell ablation techniques that are dependent on
transgene expression under the control of the CD11b16
or
the CD11c17
promoter, as both DCs and macrophages, as
well as other cell types might be affected. Hence, determin-
ing both the pattern and level of expression of multiple
cell-surface markers—F4/80, CD11b, CD11c, integrin αE
[CD103], and major histocompatibility complex (MHC)
class II (MHC II), for example—might be informative and,
if possible, is desirable. Analysis of transcription factors
typically expressed by DCs or macrophages has also been
used to characterize these cell types.15
These caveats in defining macrophages and DCs are
important to acknowledge, as they are suggestive of func-
tional overlap between these cell types, depending on
the biological context. Although DCs and macrophages
do, indeed, seem to have overlapping functions, such as
antigen uptake and presentation, several core activities of
these cell types can be considered separately.
The basic DC and macrophage paradigm
Dendritic cells
DCs represent a group of heterogeneous cell subtypes
that have critical roles in immune surveillance and the
T cell
B cell
pDC
Monocyte
Ly6C–
CCR2-mediated
recruitment
Ly6C+
pre-DC
Peripheral
blood
Draining
lymph node
Kidney
CCR7
CD11c
CD103
CLEC4K
(CD207) CLEC9ACCL19/
CCL21-mediated
relocalization
CX3CR1
GM-CSF
receptor
BDCA-2
(CD303)*
pre-DC
FLT3FLT3
FLT3LG
CDP
CSF-1R
MDP
CSF-1
(M-CSF)
FLT3LG
BoneBone marrow
CD11c
FLT3
CD103
CD11b
CSF-1R
CX3CR1
DC-SIGN
BDCA-1
Lin–
Kit (CD117)
CX3CR1
CD11bhi
F4/80
CD11clo
CD14
CD16
CD14
CD16
CCR2
CD62L
CSF-1R (CD115)
B-ATF-3
CD11b
Ly6C
CX3CR1
Ly6G
(GR-1)
CCR2
Figure 2 | The ontogeny of kidney-resident DCs and macrophages. Bone-marrow-resident MDPs differentiate into monocytes that
are released to the peripheral circulation under homeostatic and inflammatory conditions. MDPs also develop into CDPs, which
subsequently differentiate to pre-DCs that can migrate from bone marrow to the renal interstitial compartment via the blood, with
regular turnover. Under the influence of different chemokines and growth factors, the pre-DCs differentiate to form distinct, tissue-
based DC subsets (broadly characterized as CX3CR1+
DCs or CD103+
DCs) that are capable of exodus to the draining lymph
nodes where they can present antigens to B cells and T cells. Monocytes can also localize to the kidney under the influence
of chemokines such as CCR2, and subsequently differentiate into DCs. Pre-DCs also give rise to pDC, although the presence of
pDCs in kidneys of mice is disputed (dashed arrow). Abbreviations: B‑ATF‑3, basic leucine zipper transcription factor ATF-like 3;
BDCA‑(1/2), blood dendritic cell antigen (1/2); CCL(19/21), CC chemokine ligand (19/21); CCR(2/7), CC chemokine receptor
(2/7); CDP, common dendritic cell precursor; CLEC4K, C‑type lectin domain family 4 member K; CLEC9A, C‑type lectin domain
family 9 member A; CSF‑1, colony-stimulating factor 1; CSF-1R, CSF‑1 receptor; CX3CR1, CX3C chemokine receptor 1;
DC, dendritic cell; DC‑SIGN, dendritic-cell-specific ICAM‑3-grabbing non-integrin; FLT3, fms-like tyrosine kinase 3; FLT3LG, FLT3
ligand; GM‑CSF, granulocyte-macrophage colony-stimulating factor; Ly6(C/G), lymphocyte antigen 6(C/G); M‑CSF, macrophage
colony‑stimulating factor; MDP, monocyte–DC precursor; pDC, plasmacytoid DC.
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instigation of immunity or tolerance.1,18
As mentioned,
DCs originate from myeloid haematopoietic progeni-
tor cells in the bone marrow, via developmental path-
ways that exhibit considerable plasticity;19
however, DC
ontogenesis is governed predominantly by the haemato
poietic growth factor FLT3LG (Figure 2).20–22
They are
rare cells that are present in the peripheral circulation
(0.1% of total circulating leucocytes), but also reside
in virtually all tissues (especially near portals of entry),
and display broad maturational and functional diver-
sity.1,18
In keeping with their role as potent APCs, DCs
are highly proficient at both internalizing and process-
ing antigens;23
through a highly-orchestrated molecu-
lar process, the cells subsequently present peptide
fragments of processed foreign or self-antigen in the
context of MHC class I or class II molecules to T cells
that express complementary T‑cell receptors (TCRs).18
Once activated in the periphery, DCs exhibit enhanced
migratory capacity and emigrate to secondary lymphoid
organs to convey the processed antigens for T‑cell stim-
ulation, which requires both MHC–TCR interactions
and reinforcing signals induced by co-stimulatory
molecules provided by the DC.24
DC activation, matur
ation and migration are triggered by a wide array of cell-
surface receptors for Toll-like receptor (TLR) ligands,
C‑type lectins, cytokines and chemokines involved in
inflammatory responses (extensively reviewed else-
where3,20,25
). Through these mechanisms, DCs control the
initiation of naive and memory T‑cell responses,26
and
mediate a critical link between the innate and adaptive
immunological systems.1,18
Macrophages
Similarly to DCs, macrophages comprise a diverse
group of innate immune cell subsets that are particu-
larly rich in lysosomes, and are adept at phagocytosis
of tissue debris and infectious material. In addition,
macrophages can regulate other cell types by serving as
APCs, and also play a part in wound healing via the pro-
duction of an array of cytokines, chemokines and growth
factors.27
The lineage profile of macrophage precursor
populations originating in the bone marrow is similar
to that of DCs, although macrophage development, dif-
ferentiation and proliferation are primarily governed
by CSF‑1.7,28
Interestingly, postnatal administration of
CSF‑1 to mice increased kidney weight and tissue macro
phage number.29
Macrophages arise at an early stage of
organogenesis during fetal development;30
in the kidney
specifically, their presence precedes the appearance of
nephrons, and macrophage cell types seem to have a
predominantly trophic role at prenatal stages of kidney
development.30
Although the commonly accepted tenet
is that macrophage renewal within the interstitial com-
partment of solid tissues is driven by differentiation of
haematopoietic stem cells, emerging evidence suggests a
contribution from embryonic progenitor cells,31,32
as well
as in situ proliferation of tissue macrophages.9,33
The recognition that macrophages can adopt several
phenotypes led to the ‘M1’ and ‘M2’ paradigm of macro
phage development. According to this paradigm, M1
(also termed classically activated) macrophages are
regarded as proinflammatory.34
By contrast, M2 (alterna-
tively activated) macrophages are considered to promote
both wound healing and tissue fibrosis.34
These pheno-
types have been defined by in vitro experiments, and
although undoubtedly simplistic, the M1–M2 macro
phage concept emphasizes the fact that macrophages,
similar to DCs, have inherent maturational and func-
tional plasticity, suggesting that the phenotype of indi-
vidual cells and cell populations can change and evolve
over time in vivo.35
DCs/macrophages in homeostatic kidneys
Identification of renal DCs and macrophages
A range of mononuclear cells have been identified
within the renal interstitium. In addition to DCs and
macrophages, CD3+
, CD4+
and CD8+
T cells have been
isolated from unmanipulated rodent kidneys,36
as have
CD19+
B cells, CD3-
NK1.1+
cells, CD4+
CD25+
T regula-
tory (TREG
) cells37
and γδ T cells.36,38
Although murine
DCs were first described 40 years ago in the seminal
papers by Steinman and Cohn,39–41
information on the
localization, phenotype and functional characteristics
of this cell type was confined initially to DCs within
secondary lymphoid tissue. Although DCs, as well as
multiple DC subtypes, have now been described within
Box 1 | Sources of confusion in the characterization of DCs versus macrophages
Defining independent populations of macrophages and DCs (or subsets of
these cell types) for study in vivo or in vitro is often difficult, and this limitation
is relevant when considering the available data on these cell types. The factors
confounding characterization of independent macrophage and DC populations are
as follows:
Nonexclusive cellular markers
■■ For example, CD11c, F4/80 (EMR1), CD11b, and MHC class II molecules are
all co-expressed in these cell types15
■■ Furthermore, CD11c expression is induced by inflammation in macrophages,60
and neutrophils,196
as well as DCs
■■ CSF‑1R (a traditional macrophage marker) is expressed by classic DCs57
Shared cell lineage and developmental pathway
■■ Similar growth factors promote development of macrophage and DC subsets;
differentiation of these mononuclear cell types from common progenitors
requires CSF‑1, GM‑CSF and FLT3LG5,7
■■ Cell phenotype in vitro demonstrates plasticity depending on the growth factors
used
■■ CSF‑1 and CSF‑1R mutations cause marked depletion of DC populations in
experimental models57
■■ Injection of CSF‑1 into mice causes expansion of CD11c+
cells, including
macrophages, conventional DCs and plasmacytoid DCs197
■■ GM‑CSF promotes DC development in vitro; GM‑CSF produces alternative
macrophages198,199
that are associated with a ‘mature DC‑type’ cytokine profile
Functional similarity
■■ DCs and macrophages are both involved in tissue surveillance and are highly
phagocytic
■■ Many immunoregulatory factors, including cytokines and chemokines, can be
produced by both cell types15
■■ Although antigen-presenting capacity is typically attributed to DCs,
macrophages can suppress T‑cell activation in an antigen-specific manner15,200
Abbreviations: CSF‑1, colony-stimulating factor 1 (also known as, macrophage colony-
stimulating factor); CSF‑1R, CSF‑1 receptor; DC, dendritic cell; EMR1; EGF-like module-
containing mucin-like hormone receptor-like 1; FLT3LG, fms-like tyrosine kinase 3 ligand;
GM‑CSF, granulocyte-macrophage colony-stimulating factor.
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virtually all lymphoid and nonlymphoid tissues, formal
identification of renal DCs, particularly CD11c+
DCs,
had been disputed historically. The renal DC population
was thought initially to be localized within the glomer
ular compartment and, therefore, to mediate the patho-
genesis of glomerulonephritides. This assumption was
supported by the isolation of rodent glomerular cells that
were phenotypically distinct from mesangial cells, which
expressed MHC II (I‑A subclass) and exhibited T‑cell
allostimulatory capacity in primary mixed leucocyte
cultures.42–45
Concurrent rodent and human studies con-
firmed the presence of cells positive for MHC II mol-
ecules within the cortical interstitium of the kidney.46,47
Furthermore, electron microscopic examination of
rodent peritubular interstitium enabled differentiation
of fibroblasts from immune cells with features sugges-
tive of DCs (high expression of MHC II) or macro
phages (abundant primary and secondary lysosomes).48
Immunohistochemical identification of CD11c+
DCs
requires minimization of protein denaturation by avoid-
ing high temperatures;49
this technique has facilitated
the detection and localization of these cells proximate to
peritubular capillaries.50
Phenotypic characterization
In healthy mice, the renal CD11c+
DC population is
heterogeneous, expressing MHC II and low or inter-
mediate levels of CD11b and F4/80.50
Although these
markers can also be expressed by macrophages, the renal
DCs identified in mice more closely resembled splenic
dendritic cells than peritoneal macrophages with regard
to morphological, molecular (co-stimulatory molecule
expression) and functional properties.50
Furthermore,
these cells exhibited allogeneic T‑cell stimulatory capac-
ity, although to a lesser degree than observed with splenic
CD11c+
DCs.50
Extensive phenotypic characterization
revealed that conventional CD11c+
DCs (cDCs) had an
immature phenotype (low CD80 and CD86, and neg-
ligible CD40 expression) and substantial phagocytic
capacity—in addition to the absence of nonconventional
plasmacytoid DC (pDC) markers (CD8α and B220).50
CD11c+
MHC II+
renal DCs can be segregated into two
distinct subsets: integrin αE
β7
expressing and, therefore,
CD103+
(CD103+
CD11blo
CX3CR1−
F4/80−
SIRP‑α−
) cells;
and CD11b+
(CD103−
CD11b+
CX3CR1+
F4/80+
SIRP‑α+
)
cells (Figure 2).51
Both of these renal DC subsets appear
to undergo cell division and, therefore, proliferation in
homeostatic renal tissue.51
CD103+
renal DCs arise pri-
marily from bone-marrow-derived precursors, pre-cDC,
and express higher levels of DNA-binding protein inhibi-
tor ID‑2 and interferon regulatory factor 8 (IRF8) than
the CD11b+
subset, as well as FLT3.51
Indeed, both the
FLT3 receptor and its ligand, FLT3LG, are an absolute
requirement for the development of this DC subset.51
CD11b+
DCs express CSF‑1 receptor (CSF‑1R; also
known as CD115), in keeping with a developmental bias
towards this growth factor, but are also dependent on
FLT3LG for complete reconstitution.51
Although improvements in renal DC characterization
have been made, the absolute numbers of these cells that
can be isolated from the kidney remain relatively low
compared with secondary lymphoid organ DC popula-
tions;50
however, systemic administration of FLT3LG in
mice52
and nonhuman primates53
enables expansion of
both renal cDC and pDC populations in vivo. Ex vivo,
these mobilized DCs, when freshly isolated, retained
an immature phenotype and promoted the develop-
ment of IL‑10-producing TREG
cells in mixed leuco-
cyte reactions.52
Low CC chemokine receptor (CCR1,
CCR2, CCR5, and CCR7) transcript levels in these
DCs reflect a failure to migrate in vitro in response to
chemokines (CC chemokine ligand 3 [CCL3], CCL5,
and CCL20);52,54
however, their capacity to migrate to
the lymphoid-tissue-homing chemokines CCL19 and
CCL20 could be augmented ex vivo by exposure to
bacterial lipopolysaccharide (LPS).54
Although no candidate precursor has been for-
mally identified, renal-resident DCs are thought to be
derived from common DC precursors that arise from
bone marrow progenitors and subsequent blood-borne
pre-DC precursors (Figure 2)55
—as demonstrated
for CD103+
DCs.51
Nevertheless, lymphocyte antigen
6C (Ly6C)–
‘patrolling’ circulating monocytes might
also contribute to renal-resident DC populations;
Ly6C+
potential DC precursors infiltrate the kidney
under inflammatory conditions,7,9
influenced by the
CX3C chemokine receptor 1 (CX3CR1; also known as
fractalkine receptor) and CCR2.56
Macrophages, conventionally defined as CD11b+
,
express greater levels of CSF‑1R compared with the
CD11c+
DC subset.57
The CSF‑1R–enhanced green
fluorescent protein (eGFP) transgenic-reporter mouse
(the so-called ‘MacGreen’ mouse; Table 1) has been
used to track postnatal macrophage development. In
this model, cells with active gene expression driven by
the CSF‑1R promoter were demonstrated to be present
before nephrogenesis, in close apposition to developing
renal tubules, and increased in number after administra-
tion of CSF‑1.30
In adult kidneys, resident macrophages
are believed to originate from bone-marrow-resident
monocyte precursors,58
which are characterized as
lineage negative (Lin−
)cells that express CX3CR1 and the
mast/stem cell growth factor receptor Kit (also known
as CD117); additional recruitment of Ly6C+
cells can
occur under the influence of CCR2 (Figure 2).58,59
Tissue
macrophages derived from infiltrating monocytes can
undergo differentiation into the broad M1 and M2 cate
gories depending on context. Classically activated M1
macrophages are typically induced through encounter
with danger-associated molecular patterns (DAMPs)
or proinflammatory cytokines, and produce IL‑12 and
IL‑23 (as do DCs) to promote CD4+
T‑helper (TH
) cell
polarization.60,61
Alternatively activated M2 macrophages
can arise through deactivation and differentiation of M1
macrophages, or de novo, directly from infiltrating mono-
cytes;60
this subset is immunoregulatory, and produces
anti-inflammatory IL‑10 as well as Wnt7B.62
Studies in CX3CR1eGFP/+
transgenic-reporter mice
(Table 1),63
as well as the MacGreen model,64
have pro-
vided evidence of DC–macrophage network within
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the kidney. The CX3CR1eGFP/+
mouse model enables
mapping of DCs and/or macrophages derived from
CX3CR1+
monocytes emigrated from the bone marrow.
This study confirmed the homeostatic presence of renal
DCs throughout the entire interstitial scaffold, encasing
glomeruli, as well as low numbers of these cells within
the mesangial matrix.63
In the MacGreen mouse,64
macro
phages were visualized surrounding glomeruli and encas-
ing renal tubules within the medulla. The complexity of
this renal-resident DC–macrophage network has been
elegantly reinforced in a study demonstrating multi-
ple discrete cell subsets, distinguished by cell-surface
markers, cytokine production, and transcription factor
and chemokine receptor expression, in the kidney;15
the cell populations were initially defined according to
expression levels of CD11b and CD11c.15
Two defined
subsets were found to exhibit a DC phenotype, with
the ability to robustly stimulate CD4+
T‑cell prolifera-
tion, including the induction of forkhead box protein
P3 (FOXP3)+
TREG
cells.15
However, these cell types also
phagocytosed latex beads, and expressed the macrophage
marker CD68 in conjunction with developmental and
reparative growth factors, such as insulin-like growth
factor 1, platelet derived growth factor and Wnt7B.15
By
contrast, two other cell subsets displayed a macrophage
phenotype, characterized by phagocytic capability but
an absent or limited capacity to induce T‑cell prolifera-
tion.15
These macrophage cell types also expressed growth
factors and produced IL‑10 after LPS stimulation.15
Thus,
these findings reiterate the concept that overlapping DC
and macrophage characteristics should be considered in
experimental studies or transgenic mice that use a single
cell marker such as CD11b, CD11c, CX3CR1 or CSF‑1R,
as these are also all variably expressed by DC and macro
phages in the normal kidney. A further limitation of
current studies examining DCs and macrophages is that
characterization of populations of these cells is based pre-
dominantly on whole kidney, rather than compartmen-
talized tissue digests. Different renal microenvironments
could potentially be associated with distinct DC and
macrophage subtypes, leading to erroneous conclusions
regarding cell localization when whole kidney samples
are analysed; for example, glomerular macrophages
do not express F4/80, but can be identified based on
CD68 positivity.65,66
Models of macrophage and DC ablation
Various methods have been used to conditionally ablate
macrophages and/or DCs in vivo, with the aim of dissect-
ing their function in disease (Table 2). In early studies,
liposomal clodronate formed the basis for cell ablation;
this agent is toxic to many phagocytic cell types, but
particularly macrophages, and systemic administra-
tion profoundly ablated macrophage populations in the
kidney, as well as liver and spleen, such that the effects
of cell ablation might have been secondary to intra
renal or extrarenal effects.67–71
Despite these caveats, this
approach has been used to deplete DCs and macrophages
in multiple mouse and rat models of renal disease.
Selective cell ablation has been attempted using trans-
genic mice that express the human diphtheria toxin
receptor (DTR; also known as heparin-binding EGF-
like growth factor [HB-EGF]) under the control of the
CD11b16
or CD11c17
promoter, to deplete macrophages
or DCs, respectively, following diphtheria toxin (DT)
administration. Although overlapping expression of
these markers in DC or macrophage subsets as well as
other cell types suggests that multiple cell populations
are inevitably depleted (Table 2), CD11b–DTR and
CD11c–DTR mice have, nonetheless, proved highly
informative. Despite the apparent simplicity of such cell-
depletion studies, multiple caveats—in addition to the
technical caveats discussed—limit their interpretation as
many possible explanations are available for the observed
results. For example, reduced tissue injury after depletion
of CD11c+
cells could potentially be manifest through a
number of mechanisms: production of injurious factors
by the resident or infiltrating renal CD11c+
cells that were
depleted; production of protective factors by the resid-
ual surviving renal CD11c+
cells, other haematopoietic
cells or parenchymal cells subsequent to interaction
with the apoptotic corpses of ablated cells, for example;
promotion of systemic protective effects of renal or
extra-renal CD11c+
cell depletion (that is, skewing of
immune responses); a protective effect attributable to
regeneration of cell populations following transient
Table 1 | Summary of DC and macrophage reporter mice
Mouse model Mechanism Utility Cells types identified Disadvantages Ref(s)
CX3CR1eGFP/+
An exon of one
allele of Cx3cr1 is
replaced by the
open reading
frame encoding
eGFP
Fate mapping of
CX3CR1+
DCs and
macrophages that
differentiate from
bone-marrow-
derived monocytes
of the same lineage
CD11b+
MHCII+
CX3CR1+
CD11c+/−
F4/80+/−
CD103−
(approximately 90%
of the total renal DC/macrophage
population)
Does not identify the
remaining CD11b−
MHCII+
CX3CR1−
CD11c+
F4/80−
CD103+
cell population
(estimated 5% of
renal-resident DCs)
201
MacGreen An eGFP encoding
gene driven by a
CSF-1R gene
(csf1r) promoter
sequence is
engineered within
the first intron
Identification of
macrophages
Bone marrow: 50% of eGFP+
cells
are also F4/80+
and CSF‑1R+
Peripheral blood: all eGFP+
cells
express F4/80 and CD11b
Kidney: peri-epithelial macrophage-like
cells correlate with F4/80 expression
in a predominantly medullary location
Does not distinguish
cell subsets
64,
65,
202
Abbreviations: CSF-1R, colony-stimulating factor‑1 receptor; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; eGFP, enhanced green fluorescent protein.
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depletion of CD11c+
cells; or any combination of these
potential mechanisms.
Although investigators have typically used a single
cell-ablation method, the concurrent use of multiple
strategies can also be informative. For example, admin-
istration of liposomal clodronate to CD11b–DTR mice
(in the absence of DT) markedly protected against renal
ischaemia–reperfusion injury (IRI), whereas admin-
istration of DT to CD11b–DTR mice had no effect on
injury.72,73
Intriguingly, the combined administration
of both liposomal clodronate and DT provided no pro-
tection, indicating that the addition of DT removes the
protective effect of the liposomal clodronate.73
These
data suggest that the phenotype of the surviving resid-
ual cells in the kidneys of liposomal-clodronate-treated
mice, predominantly identified as CD206+
macrophages
and CD11c+
cells,73
might be key to the protective effect
observed. These potential caveats and complexities should
be borne in mind when cell-ablation models are used.
Renal DC and macrophage functions
Intrarenal activities
Cell recruitment
Renal DCs seem to mediate the recruitment of other
cell types with various immunological functions. In a
mouse model of pyelonephritis caused by Escherichia
coli, CD11c+
renal DCs are the predominant producers
of CXC chemokine ligand 2 (CXCL2), which drives the
recruitment of neutrophils to facilitate bacterial clearance
(Figure 3);74
this effect was abrogated after conditional
DC ablation in CD11c–DTR mice.74
Renal repair
The progression of disease in many experimental models
of kidney injury, such as chronic allograft and diabetic
nephropathy, can be limited through various interven-
tions, but these do not typically lead to renal regeneration.
Renal regeneration does occur, however, following mod-
erate AKI induced by renal IRI, and this setting has been
used to explore the role of macrophages in renal repair; in
particular, depletion of macrophages using either liposo-
mal clodronate75
or DT treatment of CD11b–DTR mice62
during the reparative phase of IRI-induced AKI markedly
retarded restoration of tubular integrity and renal func-
tion. Macrophage-derived Wnt7B and IL‑22 (induced
via TLR4) have been implicated as key mediators of renal
repair and tubular regeneration in this context.62,76
Fibrosis
Fibrosis is associated with progression of kidney disease
to chronic renal impairment.61,77
That macrophages can
promote the production of extracellular matrix by myo
fibroblasts and, therefore, scar formation by adopting a
‘wound healing’ M2 phenotype during inflammation is
well established (Figure 4); in the kidney, this pathway
is likely to be detrimental and, in AKI, might occur in
conjunction with other profibrotic processes, such as
epithelial cell-cycle arrest.78
Indeed, macrophages have
been implicated in the development of renal fibrosis, as
administration of liposomal clodronate was found to
be protective in the rodent unilateral ureteral obstruc-
tion (UUO) model.79,80
Interestingly, reduced fibrosis
was demonstrated in DT‑treated CD11b–DTR mice
with UUO.9,81
In contrast, ablation of CD11c+
cells in
CD11c–DTR mice with UUO did not reduce renal scar-
ring,82,83
despite the fact that increases in the maturation,
activation and antigen-presenting capacity of renal DCs
were reported in this setting.83
Studies involving the use
of bone-marrow-chimeric CD11b–DTR mice, in which
either resident renal DCs and macrophages or infiltrating
Table 2 | Rodent models of DC and macrophage ablation
Model Mechanism Utility Disadvantages
CD11c–DTR
mouse17
Simian DTR–eGFP-encoding fusion
gene inserted after the promoter of
the Itgax gene encoding CD11c;
administration of DT results in the
death of cells with active Itgax-
promoter-dependent gene
expression (that is, cell types that
are usually CD11c+
)
Short-term (48 h) ablation of 85–90%
conventional DCs in vivo, with preservation
of plasmacytoid DC compartment;203
cytotoxic T cells17
and NK cells204
were
affected to a lesser extent
B cells and macrophages were unaffected
Depleted all CD11c+
DCs
systemically, including F4/80+
cells16
Late (72 h) neutrophilia,205
which
could potentially mask the DC/
macrophage-dependent effects
Repeated systemic
administration of DT is lethal
CD11b–DTR
mouse16,206
DTR–eGFP encoding fusion gene
inserted after the promoter of the
Itgam gene encoding CD11b; DT
administration causes the death of
cells with active Itgam-promoter-
dependent gene expression (that is,
cell types that are usually CD11b+
)
CD11b+
cells predominantly affected
(also expressing F4/80);206
CD3+
T cells,
B cells, and neutrophils were not
affected73,206
Depletes 90% of CD11b+
cells
(Ly6G−
CCR2−
CX3CR1+
and
Ly6G+
CCR2+
CX3CR1−
)
systemically at 24 h after DT
administration; counts were still
low at 48 h73
Liposomal
clodronate71
Liposomes phagocytosed by
macrophages, followed by
intracellular clodronate
accumulation, which causes cell
death by apoptosis70
Depletes phagocytic cells; total
macrophage population (Ly6G+
and Ly6G−
)
decreased by 75% after 24 h73
Ly6G+
cells recover to higher than
pretreatment levels73
The CD11c+
cell population is preserved73
All cells with substantial
phagocytic capacity are
potentially affected
Clodronate leakage from dead
or dying cells might affect
inflammatory reactions69
Abbreviations: CCR2, CC chemokine receptor 2; CX3CR1, CX3C chemokine receptor 1; DC, dendritic cell; DT; diphtheria toxin; DTR, diphtheria toxin receptor
(also known as heparin-binding EGF-like growth factor); eGFP, enhanced green fluorescent protein; Ly6G, lymphocyte antigen 6G (also known as granulocyte-
differentiation antigen‑1); NK, natural killer.
REVIEWS

bone-marrow-derived cells were depleted, demonstrated
that resident renal nonparenchymal cells proliferate in
UUO, but do not actively contribute to fibrosis;9
the cells
with a profibrotic transcriptional profile expressed low
levels of Ly6C and had matured from kidney-infiltrating
‘Ly6Chigh
’ monocytes.9
In addition, persistent pro
inflammatory macrophage activation has been shown
to promote tubular atrophy and fibrosis after AKI.84
Collectively, these data suggest that macrophages, rather
than DCs, drive renal scarring.
The precise mechanism by which macrophages
promote fibrosis in the kidney remains unclear. Trans
forming growth factor β1 (TGF‑β1) is implicated in this
process, as a key profibrotic cytokine (Figure 4); however,
mice lacking expression of this cytokine specifically in
macrophages exhibited comparable levels of fibrosis to
wild-type mice with IRI-induced AKI or UUO, suggest-
ing that macrophage-derived TGF‑β1 is not critical to
fibrosis in these disease models.85
Macrophage-derived
mediators, such as the lectin galectin 3,81
might be
important to renal fibrosis, but further work is needed
to clarify their identity and role in this process.
Extrarenal DC function
Following activation, renal DCs are known to traffic to
draining lymph nodes (Figure 3), where they present
antigens. Several studies have provided additional
insights into the behaviour of these DCs when exposed
to antigenic material. CD11c+
renal DCs preferentially
and rapidly endocytose small (40 kDa) molecules,
compared with splenic DCs that predominantly endo
cytose larger antigenic material (500 kDa).86
DCs in
the kidney-draining lymph nodes also endocytose low-
molecular-weight antigens that are transported to them
by cell-independent mechanisms. Renal lymph-n ode-
based DCs, which express CD8, chemokine XC receptor
1 (XCR1; also known as the lymphotactin receptor), and
basic leucine zipper transcriptional factor ATF-like 3
(B-ATF‑3), are capable of antigen cross-presentation to
subsequently delete cytotoxic T cells in a programmed
death ligand 1 (PD‑L1)-dependent manner.87
These find-
ings imply a necessary tolerogenic function for renal DCs
that are continually exposed to innocuous antigens, such
as serum and food proteins. This hypothesis is further
supported by the finding that proteasomal process-
ing of albumin by rat bone-marrow-derived renal DCs
in vitro enables these cells to prime and subsequently
activate CD8+
T cells.88
Similar observations have been
made in rats subjected to five-sixths nephrectomy
to induce focal segmental glomerulosclerosis, which
resulted in interstitial inflammation, including infiltra-
tion of CD11c+
CD103+
DCs.88
The cell infiltrates in the
kidney were reduced in animals treated with the pro-
teasome inhibitor bortezomib.88
In this study, DCs iso-
lated from kidney-draining lymph nodes in five-sixths
nephrectomized mice activated syngeneic CD8+
T cells
in a manner that was time-dependent and reduced by
bortezomib treatment.
Systemic administration of LPS in mice initiates DC
efflux from the kidney to the draining lymph nodes over
24–72 h.89,90
Renal subcapsular placement of ovalbumin
and subsequent LPS administration results in DO11.10
(ovalbumin-specific) CD4+
T‑cell proliferation in the
ipsilateral renal lymph node, with antigen presentation
mediated by CD11c+
renal DCs.89,90
A similar DC migra-
tory response has been seen following IRI.89,90
These find-
ings are relevant mechanistically to the ex vivo analysis
of FLT3LG-mobilized renal DCs that upregulate CCR7
in response to LPS (Figure 1),54
a necessary requirement
for DC migration to draining lymph nodes, which is
mediated by CCL19 and CCL21 (Figure 2).
DCs/macrophages—roles in renal disease
Multiple rodent models of diverse clinical renal diseases
are available (Table 3), and can provide mechanistic
insights into glomerular and tubular pathophysiology
(reviewed elsewhere91
). We discuss a number of stand-
ard immunological and cytotoxin-based models of renal
disease in which the roles of DCs and/or macrophages
have been investigated extensively.
Anti-inflammatory
DC activity
Mitigation of AKI (IRI
and cisplatin)
Amelioration of NTN
Neutrophil
recruitment
Gram
negative
bacilli
Migrating
monocyte
Migration to lymph node and
presentation of antigens to T cells
DC exodus
in response
to IRI
LPS
and other
stimuli
Interstitium
Lymphatics
Peritubular capillary
Endothelium
Tubular lumen
Albumin or
albumin
fragments
Tight
junction
Proinflammatory DC activity
Cytokine secretion in IRI
Protein uptake and
antigen presentation
IL-12 secretion, intrarenal
attraction and expansion of
T cells and B cells in SLE
Intrarenal T-cell activation
Induction of TH
17 cells in UUO
Interactions with tissue-resident
cells and the influx of proteins
and immune cells dictates
DC maturation
CXCL2
CD45
CD11c
Neutrophil
Renal tubual
epithelial cell
Figure 3 | Renal DC function in health and disease. DCs perform homeostatic
functions, including induction of tolerance to peripheral antigens typically cleared
by the glomerulus, such as albumin, and anti-infection immunosurveillance.
Interaction of DCs with bacteria causes them to generate chemokines to attract
effector cells, such as neutrophils. The kidney-resident DCs also operate to
exacerbate (proinflammatory DCs) or mitigate (anti-inflammatory DCs) a wide range
of parenchymal disease, and the role of these cells in disease might be determined
by either tissue-resident cells or influxing cells and antigens. For example, the
responsiveness and maturation state of DCs might be regulated by ongoing
interactions with tubular epithelial cells. Abbreviations: AKI, acute kidney injury;
DC, dendritic cell; IRI, ischaemia–reperfusion injury; LPS, lipopolysaccharide; NTN,
nephrotoxic nephritis; SLE, systemic lupus erythematosus; TH
17, type 17 T‑helper;
UUO, unilateral ureteral obstruction.
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Glomerulonephritides
Nephrotoxic nephritis
Mice injected with antiserum produced in sheep, rabbits
or goats after vaccination with mouse renal cortex
develop rapid and progressive glomerular damage,
termed nephrotoxic nephritis. This condition mimics
the crescentic glomerulonephritis seen in human auto
immune disease.92
The glomerular-based antigen–
antibody complexes that are generated in this model are
captured by both DCs and macrophages, and are sub-
sequently presented to T cells (Table 3). The relevant
APCs within the kidney during the initial ‘injury’ phase
of nephrotoxic nephritis are typically CD11c+
CD11b+
cells with a maturing phenotype. Of note, depletion of
these cells in CD11c–DTR mice at this early stage (day 4)
exacerbated disease, suggesting an anti-inflammatory role
for renal DCs;93
however, depletion of CD11c+
cells at a
later stage (day 7) reduced the numbers of effector DCs
and T cells, and attenuated disease,93
supporting a pro-
inflammatory role of DCs as they mature and implying
a biphasic role for DCs in this disease process.93
Renal
DCs isolated from these mice induced CD4+
T‑cell pro‑
liferation ex vivo, and promoted concurrent secretion
of interferon (IFN)‑γ and IL‑10 in co-culture experi‑
ments; IL‑10 levels were elevated at day 4 and increased
over time whereas proinflammatory cytokine expression
only seemed to be increased at day 10, again support‑
ing the proinflammatory and anti-inflammatory roles of
DCs.93
Ly6G–
renal DCs, rather than cells derived from
infiltrating Ly6G+
monocytes, seem to produce most of
the proinflammatory tumour necrosis factor (TNF) and
IL12/23p40 in this model.93
Tubulointerstitial DCs have
also been shown to release the proinflammatory cytokine
IL‑1β, via NACHT, LRR and PYD domains-containing
protein 3 (NLRP3)-inflammasome–caspase‑1 pathway
activation.94
DC depletion using CD11c–DTR mice
provided additional evidence supporting a protective
role for renal DCs in nephrotoxic nephritis, by demon‑
strating that deletion of these cells at days 4 or 10 after
induction of disease aggravates the extent of injury.95
The mechanism of DC‑mediated renal protection in
nephrotoxic nephritis seems to centre on IL‑10 produc‑
tion and regulation of type 1 TH
(TH
1)-cell responses.96,97
Initial evidence suggested that this effect might be medi‑
ated via expression of inducible co-stimulatory molecule
ICOS‑L specifically on renal DCs, which could promote
IL‑10 secretion by T cells that express its co-receptor.98
Interestingly, expression of this protein by renal DCs
has been shown to decrease concomitant with increased
production of proinflammatory cytokines.93
Macrophage ablation in CD11b–DTR mice has been
shown to attenuate glomerular disease and tubular injury,
and decrease effector CD4+
T‑cell populations in crescen‑
tic glomerulonephritis models.99
Other methods of abro‑
gating macrophage function through blockade of factors
involved in either recruitment or activation of these cells,
such as CCL2, are also protective in glomerulonephritis,
suggesting a proinflammatory role for renal macro
phages.100,101
Further evidence of a proinflammatory
role for renal macrophages in glomerulonephritis comes
from a rat mesangioproliferative glomerulonephritis
model. In this model, injection of mouse monoclonal
antibody targeting thymocyte antigen 1a (Thy1.1) results
in mesangial-based macrophage infiltration.102
Other
models of glomerulonephritis induced by antibodies
targeting the glomerular basement membrane antibody
also demonstrate ingress (or localization of adoptively
transferred cells) and proliferation of monocyte-derived
macrophages within glomeruli, correlating with histo
pathological severity;103,104
these phenomena can be
reversed by inhibiting CSF‑1,105
or treatment with an
anti-CD80/CD86 monoclonal antibody.106
Podocyte immunopathology in NOH mice
In a mouse model of podocyte immunopathology, in
which antigens are expressed in glomerular podocytes
(so-called NOH mice; Table 3),107
glomerular infiltrates
observed in the experimental disease setting revealed
increased numbers of CD11c+
CD11bintermediate/high
DCs, and
CD11c−
CD11b+
macrophages, as well as proinflammatory
Stimulation of pericyte accumulation and activation,
myofibroblast differentiation, and production of ECM
Myofibroblasts
Matrix
depositionPericyte
Tubular lumen
Tight
junction
M1 macrophage M2 macrophage
Repair
of AKI
Tissue
repair
Direct
tubular
injury
Presentation
of antigens
to T cells
Monocyte recruited
to kidney interstitium
CSF-1 (M-CSF), IL-10
Macrophage
reprogramming
Wnt7b
IL-22
HO-1
IL-10
Increased adhesion
and proinflammatory
activators (ICAM-1,
osteopontin)
IL-12
IL-23
Profibrotic factors
(TGF-β, PDGF,
galectin 3)
Figure 4 | Macrophages in renal disease. Tissue-resident macrophages or infiltrating
proinflammatory monocytes can become classically activated by exposure to danger-
associated molecular patterns or proinflammatory cytokines to take on an M1
phenotype, associated with production of IL‑12 and IL‑23, engagement of T cells for
antigen presentation, activation or exacerbation of profibrotic parenchymal changes,
and direct and indirect tissue injury. M1 macrophages can be reprogrammed to
become alternatively activated M2 macrophages by stimulation with anti-
inflammatory cytokines, such as IL‑10 or CSF‑1, or ingestion of apoptotic cells. M2
macrophages might facilitate and coordinate restoration of tubular cell and, therefore,
kidney tubule integrity following injury. M2 macrophages can also express anti-
inflammatory mediators, such as HO‑1 and IL‑10, which act to limit tissue injury and
promote resolution of inflammation, but might also drive pericyte and myofibroblast
activation through production of TGF‑β, galectin 3 and PDGF. Abbreviations: AKI, acute
kidney injury; CSF‑1, colony-stimulating factor 1; ECM, extracellular matrix; HO‑1,
haem oxygenase‑1; ICAM‑1, intercellular adhesion molecule 1; M‑CSF, macrophage
colony-stimulating factor; PDGF, platelet-derived growth factor; TGF‑β, transforming
growth factor β; Wnt7b, wingless-related MMTV integration site 7B.
REVIEWS

CD11c+
Ly6G+
DCs or CD11clow
Ly6G+
macrophages in
the kidney. In this model of chronic glomerulonephritis,
DCs produced IL‑12 and upregulated the co-stimulatory
molecules CD86 and CD40, indicating activation of
these cells. In addition, the DC component, and conse-
quently the periglomerular infiltrates, rapidly resolved
after administration of DT to remove CD11c+
cells in the
progeny of NOH mice crossed with CD11c–DTR mice.107
Presentation of antigen by DCs to CD4+
T cells was shown
to occur intrarenally only, and facilitated accumulation of
CD8+
cytotoxic T lymphocytes (Figure 3).
Lupus nephritis
Systemic lupus erythematosus (SLE) is a common
autoimmune disease with a clinical predilection for
catastrophic renal involvement. Most studies in animal
models of SLE have focused on the role of systemic
DCs in disease pathogenesis. However, the role of
kidney-resident DCs and macrophages in the initiation
and progression of SLE-like disease are increasingly
described (Table 3).
NZB/W F1 mice develop lupus nephritis spontan
eously, and this disease is characterized histologically by
extensive mononuclear-cell infiltration. In this model, the
presence of CD11b+
F4/80high
CD80+
CD86+
macrophages
has been shown to correlate with disease severity,108
and
intrarenal CD11b+
CD11c+
cDCs were demonstrated to
express CXCL13 (also known as B lymphocyte chemo
attractant; Table 3) and, therefore, had the ability to
recruit autoantibody-producing B cells.109
With ageing, MRL‑Faslpr/lpr
mice also develop lupus
nephritis; in these mice, lupus nephritis correlated with
renal expression of C1q (a subcomponent of the classical
complement activation pathway), which was shown to
be generated locally by renal CD11c+
DCs.110
The pro-
inflammatory cytokine IL‑12, produced intrarenally by
both DCs and macrophages, promoted the accumulation
of IFN‑γ-secreting T cells (Figure 3), which exacerbated
nephritis in these mice.111
Not surprisingly, therefore,
MRL‑Faslpr/lpr
mice lacking IL‑12 demonstrated reduced
renal damage and decreased mononuclear cell infiltration
into the kidney compared with wild‑type MRL‑Faslpr/lpr
mice;111
by contrast, overexpression of CCL2 promoted
monocyte recruitment to the kidney, and this effect
was mitigated by blockade of the chemokine or its
receptor (CCR2).112,113
Table 3 | Experimental models of glomerular diseases with known DC and macrophage involvement
Disease model Mechanism DCs and/or macrophage function
Nephrotoxic nephritis
Various models
in which
disease is
evoked by
renal-targeting
antisera
Glomerular injury is induced through administration of
antibodies targeting the rodent kidney, which were
raised in a heterologous species (such as sheep or
rabbits) in response to injection of mouse or rat renal
cortex tissue92
Antigen–antibody complexes are endocytosed by MHCII+
DCs, which subsequently present the antigens to CD4+
T cells207,208
Macrophages are the main effector cells207
Aggravation of damage was observed after early depletion
of CD11c+
DCs95
Glomerulonephritis
NOH mice107
The promoter of the human podocyte-specific nephrin
encoding gene (NPHS1) is fused to cDNA encoding the
transmembrane domain of the transferrin receptor,
OVA, and HEL, and this construct is inserted into the
genome of C57BL/6 mice; podocyte injury is induced
as a result
Podocyte-OVA-dependent intrarenal stimulation of
systemically injected activated OVA-specific CD4+
T-helper cells and CD8+
CTL from OT‑II transgenic mice
Periglomerular tissues were infiltrated by
CD11c+
MHCII+
CD11bhi
Ly6G+
(DC-type) and CD11c–
MHCII+
CD11bhi
Ly6G+
(macrophage type) cells107
CD11c+
cells were CD86+
and CD40+
in NOH mice (but not
in non-transgenic controls)
DC were essential for maintenance of inflammation,
presenting antigen to T‑helper cells, stimulating IFN‑γ
production and recruiting CTLs
Lupus models
NZB/W F1
mice209
Lupus-prone F1 hybrid strain created by mating New
Zealand black and New Zealand white mice210,211
Mononuclear cell infiltration into the kidney was
associated with attraction of autoreactive T cells and
B cells and expansion of these lymphocytes within
draining lymph nodes117
CD11b+
CD11c+
intrarenal DCs and/or macrophages were
found to be the source of CXCL13109
B6.TC mice212
Mice are homozygous for the NZM2410 lupus-
susceptibility quantitative trait loci (Sle1, Sle2
and Sle3)
DCs from these mice demonstrate high expression of
CD40 compared to B6 controls213
DC have high T‑cell allostimulatory capacity, block TREG
activity and overexpress IL‑6114
NZM2328
mice214
Lupus-prone strain derived by selective inbreeding of
progeny of a cross between New Zealand black and
New Zealand white mice
Intraglomerular CD11c+
DCs co-localize with T cells and
probably promote autoantibody production, whereas
F4/80+
macrophages are confined to interstitial regions117
MRL-Faslpr/lpr
mice215
Mice are homozygous for the lpr mutation, which
interferes with lymphocyte apoptosis; features
generalized autoimmunity due to breakdown of
central and peripheral tolerance
Mature CD11c+
DCs observed within kidney120
DCs and macrophages in the affected glomeruli express
TLR9216
Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendritic cell; CXCL13, CXC chemokine ligand 13 (also known as B lymphocyte chemoattractant); HEL, hen-egg
lysozyme; Ly6G, lymphocyte antigen 6G (also known as granulocyte-differentiation antigen‑1); NOH, nephrin–OVA–HEL; OVA, ovalbumin; TREG
, T regulatory.
REVIEWS

B6.TC mice also develop spontaneous glomerulo
nephritis concomitant with the production of auto
antibodies. Compared to DCs isolated from B6 control
mice, DCs isolated from B6.TC mice have higher T‑cell
allostimulatory capacity and block the suppressive func-
tion of CD4+
CD25+
TREG
cells via overproduction of
IL‑6,114
in addition to facilitating B‑cell proliferation and
autoantibody production (Table 3).115
NZM2328 mice
also demonstrate a proliferative, gender-biased (female
predilection, as in SLE) glomerulonephritis.116
In this
model, renal histology is characterized by intraglomer
ular CD11c+
DCs that co-localize with T cells,117
whereas
F4/80+
macrophages are confined to peri-glomerular
regions, suggesting that intrarenal DCs might mediate
the presentation of (auto)antigen, thereby promoting
disease progression (Table 3).
Evidence from preclinical therapeutic studies
Administration of the immunosuppressant cyclophospha-
mide and/or blockade of co-stimulatory signalling (using
CTLA4-Ig fusion proteins or anti-CD40-ligand mono
clonal antibodies) in NZB/W F1 mice was associated with
a decrease in the number of CD11c+
renal DCs and remis-
sion of lupus.118
Amelioration of disease in MRL‑Faslpr/lpr
mice, which was associated with reduced macrophage and
T‑cell infiltration into the kidney, has been demonstrated
using a p38 mitogen-activated protein kinase inhibitor;119
p38-inhibitor treatment also decreased the abundance of
renal CD11c+
DCs, including those with a mature pheno
type that expressed high-mobility group protein B1.120
pDCs have also been implicated in lupus pathogenesis by
amelioration of lupus pathology in NZB mice genetically
engineered to lack pDCs through deletion of the gene
encoding IRF8, and in mice carrying a mutation in the
Slc15a4 gene, which retain pDCs incapable of producing
type I IFN.121
In perinuclear antineutrophil cytoplasmic
antibody (ANCA)-positive SCG/Kj mice that develop
rapidly progressive glomerulonephritis,122
a novel tri
azolopyrimidine derivative (NK026680) that inhibits DC
function was demonstrated to suppress multiple disease
manifestations and the development of autoantibodies,
providing additional evidence of the role of DCs in
glomerulonephritis.123
Manipulation of the humoral immune response
through DC‑mediated induction of immune tolerance
might also represent an approach to mitigating disease
in glomerulonephritis. Ligation of Fc receptors (particu-
larly low affinity IgG Fc region receptor IIb [FcγRIIb]) by
immunoglobulins, including endogenous antibodies and
immune complexes derived from lupus-prone mice, have
been shown to provide an inhibitory signal that prevents
TLR-mediated DC maturation and enhances the tolero-
genicity of this cell type.124
Furthermore, adoptive trans-
fer of immature DCs overexpressing FcγRIIb before or
after the onset of clinical lupus attenuated lupus nephritis
in MRL‑Faslpr/lpr
mice.124
Conversely, MRL‑Faslpr/lpr
mice
lacking FcγRIIb displayed greater B‑cell activity and
higher levels of DC‑derived IL‑12.125
The finding that administration of C‑reactive protein
reverses renal manifestations of nephrotoxic nephritis
in a macrophage-dependent manner suggests that this
cell type might also be a valid target in glomerulo
nephritis.126
Interestingly, immune complexes have also
been shown to suppress macrophage inflammatory
responses via FcγRIIb,127
and this effect was protective
in a cryoglobulin-associated membranoproliferative
glomerulonephritis mouse model.128
However, binding
of tissue-bound antibody or immune complexes might
also activate macrophages to produce proinflammatory
mediators via activation of various signal transduction
pathways, including spleen tyrosine kinase (SYK). In
keeping with this possibility, the SYK inhibitor fosta
matinib markedly ameliorated nephrotoxic nephritis
in rats and limited macrophage activation following
treatment with aggregated IgG.129
Acute kidney injury
IRI and cisplatin-induced kidney injury
Both IRI and administration of cisplatin can induce
tubular epithelial cell coagulative necrosis, and both
approaches have been used to study the role of renal
DCs and macrophages in AKI. CD11blow
F4/80high
DC
and CD11bhigh
F4/80low
macrophages (both differenti-
ated from Ly6Chigh
infiltrating cells) could be identified
early (3 h) following IRI, with the numbers of these cells
peaking at 24 h after IRI, and developing a predomi-
nantly macrophage phenotype.56
Although ablation
of DCs exacerbates cisplatin-induced AKI,130
a similar
DC‑mediated protective effect has been disputed in
models of IRI (Table 4).72,131
On the other hand, macro
phage ablation provided protection from renal injury in
an IRI model,132–134
and this protective effect was reversed
by adoptive transfer of the mouse macrophage cell line,
RAW 264.7.75,133
However, macrophages also seem to
have distinct phenotypes depending on time post-injury
in an IRI model: M1 characteristics predominated ini-
tially (1–3 days following reperfusion); whereas M2
skewing was observed during the proliferative repair
phase (dependent on Wnt7b62
and CSF‑1135
produc-
tion).60
Interestingly, adoptive-transfer and cell-tracking
experiments revealed phenotype switching of IFN‑γ-
stimulated proinflammatory (M1) macrophages injected
after IRI to M2 macrophages at the onset of tissue repair
in the kidney.60
The relevance of each of these macro
phage subsets to AKI is reflected in loss-of-function
experiments, which demonstrated that clodronate-
induced depletion of (M1) cells before or early after IRI
reduces kidney injury, whereas cell depletion at later time
points (when M2 macrophages predominate) delays
tissue restoration.60,136
In a variation of the DTR models described, mice that
selectively express the human DTR under the control
of the promoter region of γ glutamyl transferase 1, a
gene that is specifically expressed in proximal tubule
cells, develop AKI in response to injection of DT.135
In
this model, AKI is associated with renal infiltration of a
CD11b+
F4/80+
CD11c+
CX3CR1+
CD86+
DC/macrophage
cell type,135
and administration of liposomal clodronate
before DT exposure exacerbated renal injury, increased
mortality, and prolonged renal repair, as did concomitant
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DTR-mediated depletion of both CD11c+
DCs, macro
phages and proximal renal tubular epithelial cells.135
These data further demonstrate the role of DC and/or
macrophages for tubular recovery after AKI.
Ablation of CD11c+
F4/80+
DC/macrophages using
liposomal clodronate administered 1 day after renal IRI
aggravated injury and retarded tissue regeneration, seem-
ingly by preventing intrinsic IL‑10 release by these cells,
which was associated with increased proinflammatory
cytokine levels and persistence of an inflammatory
milieu.136
In the same model, injury was partly allevi-
ated by adoptive transfer of CD11c+
DCs.136
The protec-
tive effects of IL‑10 generated by renal DCs have been
seen in other models of AKI, including cisplatin-induced
nephrotoxicity: renal DCs were demonstrated to express
higher levels of IL‑10 following cisplatin treatment (with
concomitant increases in IL‑10 receptor 1 expression).137
Conversely, enhanced cisplatin-mediated injury was
Table 4 | Rodent models of renal injury and the effect of DC or macrophage depletion
Disease model Renal phenotype DC and/or macrophage
involvement
Effect of DC and/or macrophage depletion on disease
(by depletion strategy)
CD11c–DTR CD11b–DTR Liposomal clodronate
Acute kidney injury
Unilateral ureteral
obstruction
Fibrosis Interstitial infiltration of
CD11b+
Ly6G+
or F4/80+
DCs
No change in
fibrosis82,83
Reduced fibrosis9
Reduced fibrosis80
Decreased IFN‑γ and
IL‑17 T cells152
IRI Coagulative necrosis of renal
tubular epithelial cells
Interstitial infiltration of
neutrophils, macrophages
and CD11c+
DCs
Depletion of macrophages
before IRI is protective;
depletion at 3–5 days
post-IRI causes defective
repair60
Exacerbatory72
Protective131
Exacerbatory72
No change73
Exacerbatory136
Protective72,73,75,132
Decreased TNF
production147
Cisplatin Coagulative necrosis of renal
tubular epithelial cells; renal
excretion of cisplatin results
in concentration of drug in
cortex resulting in damage
predominantly to S3 segment
of the proximal tubule
Not described Cell depletion at time
of cisplatin treatment
exacerbated injury130
Not studied Not studied
Adriamycin Glomerular capillary
permeability; ROS-mediated
tubular damage
Adoptive transfer of
LPS-treated pDC ameliorates
disease217
Not studied Not studied Not studied
Glomerulonephritis
Nephrotoxic
nephritis
Crescentic
glomerulonephritis
DCs present renal antigens
to T cells
Cell depletion at day
4 and day 10 after
induction of nephritis
exacerbated renal
injury;95
depletion at
day 7 reduced injury93
Decreased
glomerular crescents
and proteinuria;
improved renal
function99
Decreased
proteinuria;218
CRP
treatment negated this
protective effect126
NOH mice107
Podocyte-related glomerular
pathology
Glomerular infiltration of
CD11c+
CD11b+
Ly6G+
DCs/
macrophages
Decreased
CD11c+
CD11b+
Ly6G+
cell infiltration into
the glomerulus107
Lupus nephritis
Lupus-prone
NZB/W mice
Severe glomerulonephritis
after polyI:C administration219
Glomerular infiltration of
CD11b+
Ly6G−
F4/80+
DCs/
macrophages220
Not studied Not studied Decreased glomerular
accumulation of
macrophages and
glomerular injury219
MRL-Faslpr/lpr
mice Glomerular crescent
formation, granular IgG
and C3 deposition within
capillaries, proteinuria
DC produce C1q;110
treatment with p38 MAPK
inhibitor decreases CD11c+
DC infiltrates;120
CSF‑1
deficiency protects against
lupus development221
Decreased
autoantibody
production and
disease severity222
Infectious disease
Pyelonephritis Escherichia coli-induced
renal injury74
DC-mediated production of
CXCL2 causes recruitment
of neutrophils74
Decreased neutrophil
recruitment
Abbreviations: CRP, C‑reactive protein; CXCL2, CXC chemokine ligand 2; DC, dendritic cell; IRI, Ischaemia–reperfusion injury; LPS, lipopolysaccharide; Ly6G, lymphocyte antigen 6G (also known
as granulocyte-differentiation antigen‑1); pDC, plasmacytoid DC; ROS, reactive oxygen species; TLR9, Toll-like receptor 9.
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observed in mice lacking IL‑10 expression, as well as in
chimeric mice lacking IL‑10 production only in DCs.137
CD11c+
DCs might also provide protection against
AKI by modulating the effects of additional cell popu-
lations. Findings in cisplatin-mediated AKI are con-
sistent with this hypothesis, suggesting that IL‑10
modulates increased expression of ICOS‑L on renal
DCs.130
Although not exclusively demonstrated within
the kidney, these data imply that the presence of IL‑10
may regulate CD4+
T‑cell responses.95
Indeed, the pro-
tective role of TREG
cells (both CD4+
CD25+
FOXP3+
and
CD4+
CD25+
IL‑10+
)138
induced by CD11c+
DCs follow-
ing renal IRI has been well-recognized.139–142
Moreover,
infusion of mesenchymal stem cells abrogated renal IRI
(reviewed in143
), via an effect that was partly mediated by
CD11c+
DCs.144
In particular, an immature phenotype of
tissue-resident DCs and intrarenal FOXP3+
expression
were associated with this renoprotective effect of mesen
chymal stem cells, and these features were lost after
DT‑treatment of CD11c–DTR mice; partial restoration of
these characteristics was achieved by the adoptive transfer
of CD11c+
DCs, although not if they lacked the capacity
to produce IL‑10.
Increasing evidence suggests that the cytokine milieu
associated with sterile inflammation established after
IRI is modulated by resident renal cells, including DCs
and/or macrophages and RTECs, to drive pathological
and reparative processes. In particular, RTECs have been
shown to express CSF‑1, which promotes macrophage
proliferation in situ.135,145
However, TLR-activated RTECs
limited classical macrophage activation in vitro, and the
results of antibody-based inhibition experiments sug-
gesting a role for IL‑10 in this regulatory process.146
Furthermore, a series of in vitro and in vivo experiments
demonstrated that RTECs could induce nonprogrammed,
quiescent macrophages or programmed proinflammatory
M1 macrophages to adopt a M2 phenotype that limited
acute renal inflammation and promoted repair.60
Resident
CD11c+
F4/80+
renal DC/macrophage numbers remained
static after IRI to the kidney, whereas the numbers of infil-
trating F4/80–
DCs and/or macrophages with a mature
phenotype increased.147
TNF, as well as IL‑6 and CCL2
were produced in greater quantities by the resident renal
DCs isolated from ischaemic kidneys than from control
kidneys, and in vivo depletion of DCs diminished total
TNF secretion within the renal CD45+
cell compart-
ment.147
Interestingly, renal IRI-mediated induction
of interferon regulatory factor 4 (IRF4, an inducible
inhibitor of TLR2 and TLR4 signalling) is localized to
CD45+
CD11c+
DCs/macrophages, and mice lacking
IRF4 demonstrated increased renal damage after IRI,
which was associated with increased TNF expression and
abrogated by liposomal clodronate, suggesting that IRF4
coordinates immunosuppressive effects of these cells by
restricting TNF production.148
These findings suggest
that resident renal cells dictate the immune responses that
occur in AKI through creation and modification of the
cytokines present within the injured tissues.
Cell-surface receptors that have a role in mediat-
ing AKI are often expressed concomitantly on renal
parenchymal and interstitial cells. For example, single
Ig IL‑1-related receptor (SIGIRR; also known as Toll–
IL‑1 receptor 8), modulates TLR signalling responses,
particularly APC function, in response to LPS challenge
and ischaemic renal damage.149,150
In particular, SIGIRR-
deficient mice demonstrate increased susceptibility
to tissue damage, including renal IRI, with increased
production of IL‑6, CXCL2 and CCL2, compared with
wild‑type mice.149
This response is abrogated in wild‑type
mice transplanted with Sigirr–/–
bone marrow cells after
renal IRI, as well as in Sigirr–/–
mice treated with lipo
somal clodronate,149
suggesting that SIGIRR represses the
response of renal myeloid cells to IRI, rather than RTECs.
Transplantation of Sigirr–/–
renal allografts in a fully
MHC-mismatched mouse model has also been associ-
ated with expansion and maturation of CD11b+
CD11c+
resident DCs/macrophages that prime T cells and
impede the development of CD4+
CD25+
FOXP3+
TREG
cells, supporting a negative modulatory role for this
protein in renal DCs/macrophages.151
Unilateral ureteral obstruction
UUO is a well-characterized model in which early inflam-
mation is followed by renal fibrosis. CD11c+
DCs exhibit
phenotypic maturation, and enhanced antigen presen-
tation to and activation of T cells following UUO, with
accompanying interstitial infiltration by CD11b+
Ly6G+
or F4/80+
DCs (depending on the cell-surface marker
used).82,83,152
DC depletion in CD11c–DTR mice at
various times after induction of UUO does not affect the
subsequent development of renal fibrosis,82,83
although
this feature is ameliorated by macrophage depletion in
CD11b–DTR mice,9
or by administration of liposomal
clodronate (Table 4).80
However, additional studies suggest
a proinflammatory role for DCs in UUO, as decreased
IFN‑γ and IL‑17 production by T cells was observed after
DC depletion.152
Three distinct populations of CD11b+
macrophages that express either high, intermediate or
low levels of Ly6C have been identified to differentiate
infiltrating bone-marrow-derived monocytes from tissue-
resident macrophages.9
Recruited Ly6Chi
cells differentiate
within the kidney becoming Ly6Cint
and then Ly6Clo
cells,
with the latter demonstrating a profibrotic transcriptional
profile. This finding is in keeping with data demonstrat-
ing that blockade of CCL2 or its receptor, CCR2, and thus
recruitment of inflammatory-type Ly6Chi
monocytes
impedes macrophage accumulation.153
Transplantation
The involvement of DCs and macrophages in renal
transplantation has been studied,154
but limited infor-
mation is available concerning the effects of standard
immunosuppressive agents on renal DC or macrophage
numbers and function. Both donor macrophages and
DCs are transferred within the allograft at the time of
transplantation, and subsequently host DCs and macro
phages are recruited into the transplanted kidney.155,156
Macrophages proliferate intensely within kidney allo-
grafts in the absence of immunosuppression, a process
that is promoted by CSF‑1.157
Early animal studies
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revealed a lack of MHC II antigen induction in kidney
allografts when recipients received ciclosporin, compared
with untreated transplant recipients.158
Paradoxically,
ciclosporin increased DC number and maturation status
in rats.159–162
Warm ischaemia alone leads to loss of the
CD11c+
CD11b+
CD103+
DC subset from syngeneic grafts
within 10 weeks, whereas cold ischaemia results in addi-
tional loss of the CD103−
DC subset and their replace-
ment by host CD11b+
CD11c+
CD103+
TNF+
DCs, which
is associated with progressive T‑cell accumulation and
IFN‑γ production.161
The ability of DCs to subvert the alloimmune response
following transplantation has been documented exten-
sively in the literature (reviewed in20
). Given their typi-
cally immature phenotype,52
renal DCs represent an
ideal potential source of regulatory DCs; however, use
of these cells is limited by inherent difficulties in isolat-
ing adequate populations. Nevertheless, mobilization of
mouse renal DCs using FLT3LG increased the absolute
numbers that could be isolated for subsequent infusion
before cardiac transplantation, which prolonged allograft
survival in the absence of immunosuppression.52
Macrophages are also recognized as important contrib-
utors to both acute and chronic allograft injury in animal
models. In loss-of-function studies, administration of
liposomal clodronate mitigated functional impairment
and tissue injury in a rat renal transplant model without
affecting the number or activation status of lympho-
cytes.162
Similarly, depletion of CD11b+
cells in CD11b–
DTR mice protected renal allografts from acute injury
and rejection.163
Furthermore, the pharmacological antag-
onism of the CSF‑1–CSF-1R pathway reduced macro
phage infiltration, T‑cell activation within the allograft,
acute cellular rejection and tubulointerstitial injury.164,165
Interestingly, such treatment had no effect on systemic
activation of T cells and B cells or humoral rejection that
occurred later in the renal transplant model.165
Persistent
macrophage infiltration also characterizes the develop-
ment of chronic allograft nephropathy in rodents,166
and
correspondingly, this manifestation is ameliorated by
blockade of macrophage development or activity.167,168
Renal DCs and macrophages in humans
The studies in rodent models described in the previous
sections have provided important insights in the vari-
able and plastic characteristics of renal DCs and macro
phages, and provided a basis for increased phenotypic
and functional understanding of such cells in humans.
However, consensus has not been reached on the identi
fication of distinct cell subtypes in rodents or humans
and, therefore, comparison of cell types and extrapo
lation of data from animal models to human disease is
difficult. These issues provide avenues for future research
(see Box 2). Nevertheless, our knowledge of renal DCs
and macrophages in the healthy and diseased human
kidney has expanded.
In the healthy kidney
The DC and macrophage populations present in normal
human kidneys have been studied less extensively than
those in rodents. To date, most studies in human kidneys
havefocusedondemonstratingthepresenceofDCswithin
renal parenchyma using immunohistochemistry (mainly
according to expression of blood DC antigen [BDCA]
molecules, CD68 and DC‑specific ICAM‑3-grabbing
non-integrin [DC‑SIGN; also known as CD209]).
The putative function of these cells has been extrapo
lated based on findings in animal models. Both cDCs
(BDCA‑1[CD1c]+
DC‑SIGN+
CD68+
and BDCA1+
DC-
SIGN−
CD68−
)andpDCs(BDCA‑2+
DC‑SIGN−
)havebeen
demonstrated within the normal renal interstitium and are
rarely present within glomeruli in humans.169
In renal allografts
Examination of human renal allograft biopsy samples
during acute cellular rejection has revealed an increased
number of DC‑SIGN+
DCs, particularly intraglomer
ular cells.169
Cells positive for BDCA‑1, BDCA‑2 and DC
lysosomal associated membrane protein (DC‑LAMP, also
known as CD208) have also been identified within renal
allografts during acute rejection.169
CCR1+
DC‑SIGN+
DCs
have been described in the kidney after transplantation.170
Macrophages (CD68+
cells) have also been identified in
renal allografts with histological evidence of antibody-
mediated,171,172
acute cellular173
and chronic rejection.174
Furthermore, reduced estimated glomerular filtration
rate correlated with macrophage-related gene expression
panels in renal transplant tissues obtained in biopsies
performed for various clinical indications.175
Histological
alterations reflecting interstitial fibrosis and/or tubular
atrophy as well as inflammation were also associated
with a macrophage signature in microarray analyses.176,177
Whether these data reflect a subset of macrophages associ
ated with acute rejection or a reparative phase to injury
remains unclear; nevertheless, glomerular178,179
or inter
stitial180,181
macrophage infiltration is a poor prognostic
sign and marker of unfavourable graft outcome.
Diseases of the native kidney
Macrophage infiltration has also been shown to be associ-
ated with adverse outcomes in native kidney disease; for
example,CD68+
macrophageinfiltrationisanindependent
Box 2 | Renal DCs and macrophages—future aims
■■ Consensus must be reached regarding differences and
similarities between DCs and macrophages, to enable
appropriate identification and classification of the
following types: glomerular versus tubulointerstitial;
tissue-resident versus infiltrating; immunogenic versus
tolerogenic; fibrotic versus reparative
■■ Efforts are needed to standardize the terminology
between mouse and human cells
■■ Exploration of RTEC–DC–macrophage crosstalk is
important
■■ Expansion of understanding of DCs and macrophages
in non-immunological and chronic disease processes,
such as diabetic kidney disease, is required
■■ Development of models with kidney-specific DC and/or
macrophage ablation should be a key goal
■■ Emphasis should be placed on translational research
and the applicability of findings to clinical disease
Abbreviations: DC, dendritic cell; RTEC, renal tubular epithelial cell.
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risk factor for progression to end-stage renal disease in
patients with membranous nephropathy.182
Evaluation of
biopsy tissues from patients with a diverse range of chronic
kidney diseases demonstrated that macrophage infiltration
correlated with both the degree of chronic damage and
serum creatinine levels,183
and that these cells co-localized
to areas of capillary rarefaction, implicating a role for
macrophages in microvasculature injury.184
Early studies detected CD1b+
DCs within areas of active
interstitial inflammation and glomerular crescent forma-
tion.185
Observations regarding DC infiltration have also
been made in the kidneys of patients with IgA nephrop-
athy, with the findings indicating that the number and
anatomical location of these cells alters in the disease
setting.169
In patients with lupus nephritis, increased
numbers of putative cDC that express BDCA‑1, BDCA‑3
(also known as CD141 and thymomodulin), and BDCA‑4
(CD304; neuropilin‑1) have been reported.186
BDCA‑1+
myeloid DCs were also associated with C1q in kidney
tissues from patients with severe lupus nephritis, with
concordant animal model data suggesting that intrinsic
renal myeloid DCs contribute to local C1q synthesis.110
In
human glomerulonephritis, mononuclear-cell subtypes
might be compartmentally separated, with tubulointer-
stitial cell accumulation of CD68+
DC‑SIGN+
DCs cells
and intraglomerular localization of CD68+
DC‑SIGN−
macrophages. A correlation between the number of
tubulointerstitial DCs and degree of renal injury has
also been suggested.187
Mature DC‑LAMP+
DCs are not
present in healthy kidneys but are evident at low numbers
in the kidneys of patients with renal disease, including
lupus nephritis.169,188
In addition, a study in patients with chronic kidney
disease has demonstrated increased BDCA‑3high
CLEC9A+
and BDCA‑1+
CD1a−
DC‑SIGN−
myeloid DCs, as well as
pDCs, in human kidney biopsy samples with histologi-
cal evidence of fibrosis, compared with biopsy samples
without fibrosis or healthy tissue samples.189
The myeloid
DC phenotype of some of the renal DCs observed in this
study suggests that they were derived from the peripheral
circulation, and these cells were implicated as the pre-
dominant source of the elevated TGF‑β levels in biopsy
samples from fibrotic kidneys.189
Although the presence of pDC within the diseased
kidney has been demonstrated in mouse models, the
role of these cells in human disease has been disputed.
The contribution of pDC to renal pathology has been
demonstrated most consistently in lupus nephritis,
where secretion of IL‑18 by resident glomerular cells is
a potent chemoattractant for IL‑18-receptor-expressing
pDC.190,191
BDCA‑2+
ChemR23 (Chemokine receptor-
like 1)+
pDC have been demonstrated to be present in the
kidney in the context of severe lupus nephritis.186
pDC
are also reported to be evident in increased numbers in
kidney transplants with delayed graft function, com-
pared with the setting of nephrotoxicity associated
with calcineurin inhibitors, in which the myeloid DCs
are preponderant.192
Cross-talk between T cells and DCs is well-recognized
in mouse models, and evidence from human kidney
samples suggests that a similar inter-relationship is
involved in the initiation of immunological responses
in the kidney. In particular, biopsy tissues from patients
with ANCA-associated vasculitis revealed a close prox-
imity between CD3+
T cells and DC‑SIGN+
DCs.193
Furthermore, clusters of CD21+
follicular DCs that
express the B‑lymphocyte-specific chemokine CXCL13
have also been demonstrated in tertiary lymphoid struc-
tures that develop within the renal parenchyma follow-
ing chronic antigen stimulation (in the setting of renal
allografts),194
and neolymphangiogenesis with admixed
CD4+
T cells, CD8+
T cells, CD20+
B cells, S‑100+
cDCs
and pDCs.195
These observations suggest that intra
renal antigen presentation by DCs to T cells and B cells
promotes chronic, immune-cell-mediated inflamma-
tory responses in various kidney diseases; thus, renal
DCs (and/or macrophages) probably have key roles in
mediating kidney disease.
Conclusions
Renal DCs and macrophages are phenotypically and
functionally heterogeneous cells that regulate tissue
responses to renal injury and disease. The considerable
overlap between DCs and macrophages represents a con-
tinuum of phenotype, as well as plasticity of cells of the
myeloid–monocytic lineage both in vivo and in vitro. Our
knowledge of renal DC and macrophage function lags
behind that described for these cell types in other organs;
however, progress has been made in addressing this limi-
tation through advances in cell isolation, identification,
in vivo propagation and the use of innovative genetically-
modified mouse models. The central role of renal DCs
and macrophages in homeostasis, as well as their capacity
to modulate physiological function to drive immune or
nonimmune disorders, is increasingly recognized. These
cells provide a reservoir for ongoing immunosurveil-
lance within the renal tubulointerstitium extending to
the draining lymph nodes, in addition to affording an
immune privileged site within the glomerulus.
Extensive small-animal work has provided an impor-
tant basis for increased phenotypic and functional
understanding; however, a consensus regarding precise
cell identification and extrapolation to human kidney
disease is lacking, providing avenues for future research.
Importantly, after several decades of research the ques-
tion of whether renal DCs and macrophages constitute
sufficiently specific targets for therapeutic intervention
to potentially ameliorate kidney disease progression
remains, necessitating further study.
Review criteria
A search for original, peer-reviewed articles was
performed in MEDLINE and PubMed in November 2013
and again in February 2014. The search terms used,
alone and in combination, were “kidney”, “dendritic
cells”, “macrophages”, “glomerulonephritis”, “acute
kidney injury”, “lupus”, “fibrosis” and “transplantation”.
All articles identified were English-language, full-text
papers. The reference lists of the identified articles were
searched for further relevant papers.
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Acknowledgements
The work of the authors is supported by the NIH grants
R01HL108954 and R01HL112914 (J.S.I.), and
R01AI67541 and U01AI51698 (A.W.T.); the University
of Pittsburgh O’Brien Kidney Pilot Award (J.S.I.); the
Cunningham Trust, the Mrs A. E. Hogg Charitable Trust,
Kidney Research UK and the UK Medical Research
Council (J.H.); an American Heart Association
Postdoctoral Award (13POST14520003) and an
American Society of Transplantation/Pfizer Basic
Science Fellowship (N.M.R.); and a Wellcome Trust
Intermediate fellowship (D.A.F.). The work of J.S.I. is
also supported by the Institute for Transfusion
Medicine, the Haemophilia Center of Western
Pennsylvania, and the Vascular Medicine Institute.
Author contributions
J.S.I. contributed substantially to discussion of
content and reviewed/edited the manuscript before
submission. All other authors made substantial
contributions to all stages of the preparation of the
manuscript for submission. A.W.T and J.H. contributed
equally as senior co-authors.
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