1) Microglia are the resident macrophages of the central nervous system (CNS) that originate from embryonic progenitors and self-renew, whereas peripheral macrophages can infiltrate the CNS from the blood under inflammatory conditions. 2) The triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by microglia and regulates phagocytosis and tissue repair. Loss of TREM2 function causes an early-onset dementia. 3) Mutations in TREM2's ligand-binding domain associated with Alzheimer's disease may dysregulate microglial activation by altering ligand recognition.

1. Monica
J
Carson
(monica.carson@microglia.org)
Microglia
as
a
CNS-­‐specific
9ssue
macrophage:
TREM2
dependent
func9ons
TREM2
DAP12/
TRYROBP
Tmem176b
C1qA
!
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2. Microglia are a distinct CNS-specific myeloid lineage
but the CNS is also served by infiltrating myeloid cells
B. IC LPS injection
CD45 à
MG MP
A. Untreated, no inflammation
CD45 à
FcRà
MG
FcRà
1) CNS-resident Microglia
Microglia are:
ü CD45lo to CD45intermediate
ü long-lived,
ü largely self-replenishing
ü PU.1/IRF8 dependent lineage that
begin populating the CNS during
embryonic development
ü Do not traffic to draining lymph nodes
(at detectable rates)
2) Peripheral monocytes /macrophages
that acutely infiltrate the CNS
These cells are:
ü CD45hi
ü short lived
ü rapidly replaced by bone marrow
derived cells in the adult
ü Can traffic to draining lymph nodes

3. Trem1
Trem2
Macrophage
Trem2
Trem1
Microglia
Bkgrd
Bkgrd
mg
100
101
102
103
104
FL2-H
MJC050212.039 11.8
MJC050212.030 11.4
MJC050212.021 15.7
MJC050212.012 11.2
live no boxes
MJC050212.011
Event Count: 27279
100
101
102
103
104
FL4-H
100
101
102
103
104
FL1-H
CD45 à
FcRà
C. IP LPS injection
MP
MG

4. So what do we know about TREM2 and neuroinflammation:
TREM2 up regulated
Cuprizone
Facial Axotomy
In general, situations with increased cell
damage, changes in neuronal activity and/or
TNF lead to increased microglial expression of
TREM2
Cell debris or TNF alone each are sufficient to
increase microglial expression of TREM2
(Schmid et al. JNC 2002, 2009)
Melchior et al. ASN NEURO 2010)
Please note the gene:
DAP12 = TYROBP = KARAP
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%('(,9:;
< < <= = =
!0000>000!0000>0000!0000>000!0000>0000!0000>0000!000>
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!"
#"
$"
%"
&"
'!"
'#"
'$"
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(")*+,-." /")*+,-." '0")*+,-."
*# Trem2
Blue=non-transgenic wild-type; Red=APP23 transgenic

5. :
Why focus on TREM2 in AD Associated Neuroinflammation?
Because
Trem2
is
a
receptor
that:
1) 10-­‐50
fold
higher
on
microglia
than
on
blood-­‐derived
macrophages
2) In
the
murine
CNS
is
only
expressed
by
microglia
(no
TREM2
in
PU.1
KO’s
lacking
microglia)
3) Inhibits
signaling
of
some
pro-­‐inflammatory
receptors
(TLR4)
4) Increases
phagocytosis
of
cell
debris
and
amyloid
by
microglia
5) promotes
9ssue
repair
following
injury
and
inflammatory
insults
(Overexpression
&
an9body
blocking
studies)
6) TREM2
binding
ac9vity
(puta9ve
TREM2
ligands)
expressed
by
microglia,
CNS-­‐
infiltra9ng
macrophages,
ac9vated
glia
and
stressed
&
apopto9c
neurons
and
glia
Loss of functional TREM2 signaling
leads to early onset cognitive dementia
(20’s) & death by the 40-50’s:
Nasu-Hakola Disease
Tempting to speculate that normal age-
related decrease in TREM2 levels
contributes to age-related susceptibility
for AD
(Thrash et al. 2009)
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B:TREM2
PD2
3mo.
PD21
PD7
Bkgrd
5*$6*738
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!"
"
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!"#
!"$
!"%
!&'(
)*+,-./*0
9:;<
9:==>
A.

6. Microglia are the tissue macrophage of the brain….
So, what are the roles and functions of the typical tissue macrophage?
Is the recent AD-associated mutation in TREM2 ligand binding domain, loss of function or altered
recognition of ligands leading to dysregulated TREM2 dependent microglial activation?
Phagocytosis
Antigen-presentation
To T cells: activate,
retain direct effector
functions
Trafficking to lymph nodes
Tissue homeostasis
Tissue repair
Pathogen defense
Microglia not detected to
traffick to cervical lymph
nodes
Microglia: yes
TREM2 regulated
Microglia: Yes:
TREM2 regulated
Microglia: Yes via
innate and adaptive
immunity
TREM2 regulated
Microglia: Yes,
But as inhibitory/
tolerogenic APCs
TREM2 regulated in vitro
Microglia: Yes, very
active innate immunity
and oxidative pathways
TREM2 regulated

7. TREM2 immunoreactivity: a caution
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Microglia also produce soluble “decoy” form of receptor!
Therefore reports of TREM2 immunoreactivity on non-microglia might reflect detection
of the soluble variant of TREM2 binding these TREM2 ligands on neurons, glia and
perivascular macrophages
Unpublished results, Schmid et al. 2002, Hamerman et al 2006,
Piccio et al. 2008, Hsieh et al.2009
TREM2 binding activity (putative
ligand expression) is detected on
reactive astrocytes, infiltrating
macrophages (high levels) and
stressed and/or apoptotic neurons,
reactive and apoptotic glia

8. NINDS
UCR Div of Biomed Sci PIC grant
UCR Chancellor’s Strategic Initiative
Dana Foundation
Biogen Idec, Merck
DOD; CRCC
Tammy Kielian
Caroline Whitacre
Emma Wilson
Kathryn Jones
Virginia Sanders
Marco Colonna
Harald Neuman
Jenny Ting
Carson Lab
Tiffany Butts
Deirdre S. Davis
Alfredo Hernandez
Benoit Melchior
Yoshinori Otani
Shweta Puntambekar
Victoria Senechal
Christoph D. Schmid
J. Cameron Thrash
Iryna M. Ethell
Tina Bilousova
Slawomir Sloniwski
Peter Hickmott
Devin Binder
Mike Hsu
Microglia and Macrophages in brain
development and neuroinflammation