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284 Part IV: Molecular and Cellular Hematology Chapter 19: The Inflammatory Response 285

sensorium, and the production of fibrinogen, serum amyloid protein, ineffective. Chemokine decoy receptors can also be derived in situ from
C3, C4, and C-reactive protein by hepatocytes and other cell types. previously active receptors in sites of inflammation. IL-10 facilitates
The biochemical fingerprints of an acute-phase response are revealed maintenance of CCR1, CCR2, and CCR5 expression, but induces the
through several widely available laboratory tests (C-reactive protein functional inactivity of these receptors thus hastening the resolution of
measurement, serum protein electrophoresis). Severe, overwhelming inflammation.
infections attended by high serum concentrations of endotoxin can
4
induce very high concentrations of TNF-α, IL-1β, and IL-6. High con- NEUTROPHIL APOPTOSIS
centrations of TNF-α are directly responsible for several of the key man-
ifestations of severe sepsis and septic shock (e.g., cardiac suppression, Contrary to a long-held belief that extravascular neutrophil life spans
intravascular thrombosis, capillary leakage and insulin resistance). 3,4 are fixed, recent studies suggest that neutrophil life spans can be mod-
5
Interruption of TNF-α has been a therapeutic strategy in localized ulated by local mediators. Low concentrations of macrophage-derived
inflammatory conditions like the joint inflammation (and destruction) TNF-α and Fas-ligand prolong neutrophil life span, whereas high con-
5
of rheumatoid arthritis and bowel wall inflammation in Crohn disease centrations of the same ligands lead to shortened life spans. The latter
30
and ulcerative colitis, as well as in severe sepsis and septic shock. Anti– results in neutrophil apoptosis via phosphoinositide 3-kinase–triggered
TNF-α therapy (via engineered monoclonal antibodies [infliximab and oxygen metabolite generation and Btk-NADPH–modulated pathways.
adalimumab] that neutralize TNF-α as well as inhibitory soluble TNF Other local regulators of neutrophil apoptosis include oxygen tension-
receptors [etanercept]) has been effective in conditions such as rheu- modulated hypoxia-inducible factor 1α and granulocyte-macrophage
matoid arthritis and inflammatory bowel disease, but not in severe sep- colony-stimulating factor (GM-CSF). 5
sis or septic shock in humans. Major adverse events associated with In turn, apoptotic neutrophils attenuate inflammation via the
4,30
anti–TNF-α therapies include an increased risk of mycobacterial infec- secretion of annexin A1, which inhibits the recruitment of additional
tion, development of autoantibodies (but not autoimmune disease), neutrophils as well enhances neutrophil apoptosis and phagocytosis by
5
30
and injection site inflammation. There have been isolated reports of macrophages. Lactoferrin, a neutrophil secondary granule protein, also
cytopenias, skin cancer and worsened congestive heart failure. 30 inhibits neutrophil recruitment and induces apoptosis following its release
into the inflammatory milieu. (The effect of lactoferrin on neutrophil sur-
vival is influenced by its degree of iron saturation.) Macrophage inges-
RESOLUTION OF INFLAMMATION tion of apoptotic neutrophils is called “efferocytosis,” a process directed
by distinct “find me” and “eat me” signals. “Find me” signals include the
5
Since the advent of morphologic examinations of tissue from inflamma- nucleotides ATP and uridine triphosphate (UTP), fractalkine (CX CL1),
3
tory lesions, it has been recognized that resolution of acute inflamma- lysophosphatidylcholine and sphingosine-1-phosphate (S-1-P). The cor-
tion is marked by the disappearance of neutrophils and the engulfment responding counterreceptors for these “find me” signals include P2Y2
of cellular debris by recruited monocytes and tissue macrophages. receptors, CX CR1, G2A, and S-1-P receptors, respectively. This set of
1–5
3
It has been relatively recent that resolution of inflammation has been “find me/eat me” ligand receptor pairs fits within a larger set of apoptotic
5
understood to be an active process. Key aspects of resolution include: cell-efferocyte interactions. In some cases, apoptotic cell “find me” mol-
(1) cessation of neutrophil influx effected by chemokine inactivation ecules are expressed as a function of apoptosis per se, whereas in other
and sequestration; (2) neutrophil apoptosis; (3) functional polariza- cases, existing surface molecules are either modified or linked with medi-
tion or switching of macrophages from a proinflammatory (M1) to a ators that facilitate recognition and ingestion by efferocytes.
wound-healing and tissue-remodeling (M2) phenotype; and (4) the
rapid, localized generation of proresolution lipid mediators that include
lipoxins, resolvins, and protectins. 5 M1 AND M2 MACROPHAGES
It was recognized during the 1980s and 1990s that various cytokines
5
INACTIVATION AND SEQUESTRATION can differentially modulate macrophage function. From original
OF CHEMOKINES specific observations of an IFN-γ–activated macrophage phenotype
and an IL-4–activated macrophage phenotype, emerged the concept
As described in the preceding section, neutrophil influx into an inflam- of “classical, IFN-γ–activated, M1” macrophages and “alternative,
5
matory site is in part mediated by locally generated chemokines. The IL-4–activated, M2” macrophages. Such macrophages are sometimes
actions of proinflammatory chemokines are terminated as a result of described as being “polarized” by IFN-γ, IL-4, or other mediators. Sev-
their cleavage into inactive fragments and through sequestration or eral different activated macrophage “phenotype signatures” have been
removal from participation by binding to indigenous nonfunctional elucidated, a recognition that has led to a series of designations with
decoy receptors or to locally generated decoy receptors. Examples “M1” and “M2” representing the most extreme differences. There are
5
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include the cleavage of neutrophil-directed CXC-chemokines within several M2 subtypes. IFN-γ–activated macrophages (M1) produce
a critical ELR motif by macrophage-derived matrix metalloproteinase tissue-toxic radicals (e.g., NO) and proinflammatory cytokines (e.g.,
12 and matrix metalloproteinase cleavage of the monocyte-directed TNF-α), whereas M2 macrophages produce less NO and more IL-10
CC-chemokine, CCL7. Cleaved CCL7 can still bind its cognate recep- and TGF-β, the latter being important mediators of wound healing and/
5,31
5
tors, CCR1, CCR2, and CCR3, but these cells are not mobilized by the or tissue-remodeling. Insight into the role of tissue macrophages in the
truncated version of CCL7. 5 resolution of active inflammation and the transition to wound-healing
Chemokine receptors that lack an intact highly-conserved DRY and tissue-remodeling has helped foster the concept of inflammation as
motif, which normally links the receptor to key signal transduction an actively regulated response.
molecules, function as decoy receptors. The best understood of these are
5
the “Duffy antigen receptor for chemokines” (DARC) and D6. DARC is LIPID REGULATORS: RESOLVINS
expressed by endothelial cells at sites of leukocyte egress and binds both
CC and CXC chemokines. Functional studies reveal that disruption of AND PROTECTINS
DARC leads to increased neutrophil recruitment into sites of inflamma- The transition from peak acute inflammation, marked by maximum
tion. D6 binds several different CC chemokines, thus rendering them concentrations of neutrophils, toward resolution, is accompanied by

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