The document summarizes inflammatory responses and their role in innate immunity. When barriers like the skin are damaged, resident cells release signals that trigger inflammation - characterized by redness, swelling, heat and pain. This response recruits leukocytes and tries to resolve infection or damage through pathogen clearance and healing. However, chronic inflammation from persistent triggers can lead to long-term issues like arthritis or disease.

1. Inflammatory Responses
• When the outer barriers of innate immunity—
skin and other epithelial layers—are damaged,
the resulting innate responses to infection or
tissue injury can induce a complex cascade of
events known as the inflammatory response.
• Inflammation may be
– acute (short-term effects contributing to combating
infection, followed by healing)—for example, in
response to local tissue damage—or
– chronic (long term, not resolved), contributing to
conditions such as arthritis, inflammatory bowel
disease, cardiovascular disease, and Type 2 diabetes.

2. • The hallmarks of a localized inflammatory
response were first described by the Roman
physician Celsus in the first century AD as--
rubor et tumor cum calore et dolore
(redness and swelling with heat and pain).
• An additional mark of inflammation added in
the second century by the physician Galen is
loss of function ( functio laesa).

3. These symptoms reflect
– an increase in vascular diameter (vasodilation),
resulting in a rise of blood volume in the area.
Higher blood volume heats the tissue and causes it
to redden.
– an increase in vascular permeability, leading to
leakage of fluid from the blood vessels, resulting in
an accumulation of fluid (edema) that swells the
tissue.
– Within a few hours, leukocytes enter the tissue
from the local blood vessels.

4. • These hallmark features of inflammatory
responses reflect
– the activation of resident tissue cells—
macrophages, mast cells, and dendritic cells—by
PAMPs and DAMPs to release chemokines,
cytokines, and other soluble mediators into the
vicinity of the infection or wound.
– Recruited leukocytes are activated to phagocytose
bacteria and debris and to amplify the response by
producing additional mediators.

5. • Resolution of this acute inflammatory response
includes
• the clearance of invading pathogens, dead cells, and
damaged tissue;
• the activation of the systemic acute phase response
and additional physiological responses, including the
initiation of wound healing; and
• the induction of adaptive immune response
• However, if the infection or tissue damage is not
resolved, it can lead to a chronic inflammatory
state that can cause more local tissue damage
and potentially have systemic consequences for
the affected individual.

6. Inflammation Results from Innate Responses Triggered
by Infection, Tissue Damage, or Harmful Substances
• When there is local infection, tissue damage, or
exposure to some harmful substances (such as
asbestos or silica crystals in the lungs),
– sentinel cells residing in the epithelial layer (macrophages,
mast cells, and dendritic cells) are activated by PAMPs,
DAMPs, crystals, and so on to start phagocytosing the off
ending invaders (Figure 5-17).
– The cells are also activated to release innate immunity
mediators that trigger a series of processes that
collectively constitute the inflammatory response.

8. • The recruitment of various leukocyte populations
to the site of infection or damage is a critical early
component of inflammatory responses.
• PRR signaling activates resident macrophages,
dendritic cells, and mast cells to release the initial
components of cellular innate immune
responses, including
– the proinflammatory cytokines TNF-α, IL-1, and IL-6;
– chemokines;
– prostaglandins (following the induced expression of the
COX2 enzyme); and
– histamine and other mediators released by mast cells.

9. • These factors act on the vascular endothelial cells
of local blood vessels, increasing
– vascular permeability and
– the expression of cell adhesion molecules (CAMs) and
chemokines such as IL-8 ( chemoattracts cells to
infection site).
• Cells flowing through the local capillaries are
induced by chemoattractants and adhesion
molecule interactions to adhere to vascular
endothelial cells in the inflamed region and pass
through the walls of capillaries and into the
tissue spaces, a process called extravasation.

10. • Neutrophils are the first to be recruited to a
site of infection where they enhance local
innate responses, followed by monocytes that
differentiate into macrophages that
participate in pathogen clearance and help
initiate wound healing.
• The affected epithelium is said to be inflamed
or activated.

11. • In addition to these key events at the site of
infection or damage, the key cytokines made
early in response to innate and inflammatory
stimuli—TNF-α, IL-1, and IL-6—also have systemic
effects:
– induce fever (a protective response, as elevated body
temperature inhibits replication of some pathogens)
– they do so by inducing COX-2 expression, which
activates prostaglandin synthesis; Prostaglandin E2
(PGE2) acts on the hypothalamus (the brain center
controlling body temperature), causing fever.
– These three proinflammatory cytokines also act on the
liver, inducing the acute phase response, which
contributes to the resolution of the inflammatory
response.

12. Proteins of the Acute Phase Response Contribute to
Innate Immunity and Inflammation
• Researchers noted changes in the concentration of several serum
proteins during the acute phase of the disease, the phase
preceding recovery or death.
• The serum changes were collectively called the acute phase
response (APR), and the proteins whose concentrations rise during
the acute phase are still called acute phase response proteins (APR
proteins).
• The physiological significance of some APR proteins is still not
understood, but we now know that some contribute to the innate
immune response to infection.

13. • The acute phase response is induced by
signals that travel through the blood from
sites of injury or infection.
• The proinflammatory cytokines TNF-α, IL-1,
and IL-6 are the major signals responsible for
induction of the acute phase response.
•
• They act on hepatocytes in the liver, inducing
them to secrete APR proteins at higher levels.

14. • Among APR proteins are
– many components of the complement system, which
contribute to both innate and adaptive immune
responses, and
– other proteins that function as opsonins, enhancing
phagocytosis.
• Several other proteins are produced at higher
levels during the APR.
– Mannose-binding lectin (MBL):
• is a collectin
• recognizes mannose-containing molecular patterns on
microbes and
• promotes phagocytosis by blood monocytes.
• When MBL binds to the surface of microorganisms it also
initiates complement activation

15. – C-reactive protein (CRP):
• An important APR made in the liver
• belongs to a family of pentameric proteins called
pentraxins that bind ligands in a calcium-dependent
reaction.
• ligands recognized by CRP are a polysaccharide found
on the surface of pneumococcal bacteria and
phosphorylcholine, which is present on the surface of
many microbes.
• CRP is an opsonin and also activates a complement-
mediated attack on the microbe.
• Circulating CRP levels are considered an indicator of
the level of ongoing inflammation.

16. – Serum amyloid protein and PTX
• Two other pentraxins
• similarly function as both opsonins and activators of the
complement pathway.
– Surfactant protein opsonins SP-A and SP-D
• Also released into the blood at higher levels providing
protection against lung infections,
– A number of proteins that participate in or regulate
the coagulation (clotting) pathway, such as fibrinogen.
• While most of these APR proteins are always
present in the blood at low levels, their increased
concentrations during the acute phase response
provide enhanced protective functions during
infections.

17. • With the combined defenses mounted by innate
and inflammatory responses, together with those
of the later- arising adaptive immune responses,
most infections are eliminated.
• Immune and inflammatory responses generally
are self-limiting, so once the pathogen and
damaged tissue are cleared, inflammation
usually diminishes and the tissues heal.
• However, persistence of pathogens (e.g., in
tuberculosis) or other harmful substances (e.g.,
monosodium urate crystals in gout) can cause
chronic inflammation and continuing tissue
damage and illness.