Page 308 - Williams Hematology ( PDFDrive )

282 Part IV: Molecular and Cellular Hematology Chapter 19: The Inflammatory Response 283

neutrophil adhesion than do CD11a/CD18 and CD11b/CD18. Inter- soluble mediators can provide the motive trigger for this process. 2,3,19
cellular adhesion molecules are found on a variety of cell types other Chemotactic factors for neutrophils include peptides derived from
than endothelial cells. The roles of CD11c/CD18, CD11d/CD18, bacteria (e.g., N-formyl peptides), complement-derived peptides (e.g.,
and ICAM-3 in leukocyte–endothelial adhesion are less-well estab- C5a), cell membrane-derived chemotactic lipids (e.g., PAF), and cytok-
lished. β -Integrins, notably VLA-4, are found primarily on chronic ines and chemokines produced by a variety of cell types (e.g., CXCL8
1
inflammatory leukocytes (e.g., lymphocytes, monocytes, basophils, [IL-8] from endothelial cells). 2,3,19 Chemotactic factors vary with respect
and eosinophils) and mediate leukocyte binding via VCAM-1. 2,3,9 β - to their specificity for different types of leukocytes. For example, C5a
1
Integrin–mediated adhesive interactions occur via arginine- and N-formyl peptides both induce neutrophil and monocyte chemo-
glycine-aspartic acid peptide sequences (RGDs) displayed by VCAM-1, taxis, and CXCL8 [IL-8] induces neutrophil chemotaxis, whereas CCL2
as well as on exposed surfaces of matrix molecules (e.g., fibronectin). (monocyte chemoattractant protein [MCP]-1) induces chemotactic
β -Integrin–ICAM-1 and β -integrin–VCAM-1–mediated adhesive responses in monocytes and a specific subset of memory T lympho-
2
1
3
interactions occur later (hours to days) in the inflammatory response cytes. The Th17 subset of CD4 T-helper lymphocytes secretes IL-17 and
3
than do selectin-mediated interactions. IL-22 which participate in the recruitment of neutrophils. (There are
β - and β -integrins are clearly important in leukocyte recruit- several species of IL-17, including homodimers IL-17A–IL-17F as well
2
1
20
ment into sites of acute and chronic inflammation. Eighteen different as heterodimeric species. ) Each of these chemotactic factors activates
integrin α subunits, eight integrin β subunits, and 24 in vivo heterod- “target” cells by engaging specific cell surface receptors, which, in turn,
17
imer combinations have been identified in mammals. In addition to are linked to the contractile cell motility apparatus. 3,19
leukocyte–endothelial cell adhesion interactions, integrins function in In addition to chemotaxis, soluble and cell-surface mediators
a variety of other cell–cell and cell–extracellular matrix interactions. induce leukocyte activation manifested by a wide array of changes in
A large number of integrin-targeted small molecule, peptide, and cellular function (e.g., leukocyte integrin upregulation and increased
designer antibodies have been developed for therapeutic applications. binding affinity [e.g., CD11b/CD18], selectin shedding [e.g., L-selectin],
17
Inflammatory–immunologic diseases treated with integrin antagonists lysosome degranulation, and initiation of the respiratory burst). There
include, among others, multiple sclerosis, Crohn disease, and age-re- have been great advances in understanding of the biochemical pathways
21
lated macular degeneration. involved in chemotaxis, cell activation, and degranulation. Although
High-affinity stationary adhesive interactions precede leukocyte there are many nuances in the signal transduction pathways involved in
transmigration across the endothelium into the subjacent interstitium. these processes, several themes have emerged. Cell surface receptors are
The functional importance of complementary leukocyte–endothelial activated by specific ligands (e.g., C5a, leukotriene B [LTB ], CXCL8
4
4
adhesive interactions has been clarified by in vitro binding studies and in [IL-8] and receptor activation is transduced via specific G proteins and
vivo studies that have employed neutralizing antibodies directed against membrane-associated phospholipases, which leads to mobilization of
adhesion molecules, pharmacologic antagonists of adhesion molecules, intracellular calcium, influx of extracellular calcium and phosphory-
19
2,3
and knockout mice. The functional importance of leukocyte integrins lation of series of cytosolic proteins. Rare genetic diseases linked to
(CD11a/CD18, CD11b/CD18, CD11c/CD18) has also been highlighted receptor and effector defects (e.g., IFN-γ receptor defects and nicoti-
by clinical and experimental observations in patients with rare genetic namide adenine dinucleotide phosphate [reduced form] [NADPH]
leukocyte adhesion deficiencies (Chap. 66). oxidase defects) have provided insight into leukocyte function and the
β -Integrin ICAM-1 and ICAM-2, as well a β -integrin (VLA- importance of such specific activities in host defense (Chap. 66).
1
2
4) VCAM-1, induce adhesive interactions that lead to cytoskeletal A principal result of neutrophil and monocyte recruitment is pro-
reorganization in leukocytes that flatten and spread out on the endo- vision of large numbers of activated leukocytes that can release lytic
thelial surface, extend pseudopodia between endothelial cells, and substances and reactive oxygen and nitrogen intermediates needed to
migrate along extravascular chemotactic gradients. Most leukocytes destroy foreign invaders, and a vehicle to contain foreign particulates
exit the vascular space between adjacent endothelial cells (paracellu- through phagocytosis. Some recruited monocytes differentiate into
lar transmigration). Paracellular transmigration depends not only on macrophages and recruited effector and memory lymphocytes play piv-
3,6
integrin-ligand interactions but also on CD31 (PECAM-1 [platelet- otal roles in the adaptive immune response. The products and func-
endothelial cell adhesion molecule-1]) expressed on both leukocytes tions of activated inflammatory cells are at once salutary because they
and endothelial cells, and transient reversible disassembly of tight inter- contain and destroy invaders and deleterious because they cause tissue
endothelial vascular endothelial (VE)–cadherin junctional complexes. damage. The roles of neutrophil apoptosis (programmed cell death) in
18
There is evidence that leukocytes can also exit the vascular space via a the termination of acute inflammatory responses and IFN-γ–driven M1
less-well-characterized transcellular pathway. macrophages and IL-4/IL-13–driven M2 macrophages in the transition
of an inflammatory milieu to a wound-healing or tissue-remodeling
Leukocyte Chemotaxis and Activation milieu are discussed in “M1 and M2 Macrophages”.
Leukocytes bound tightly to endothelium emigrate from the vascular Leukocyte activation, especially of neutrophils and mononu-
space into the interstitium by extending pseudopods between intercellu- clear phagocytes, results in the secretion of microbicidal peptides
lar junctions (see Fig. 19–2). Secreted neutral proteases such as elastase, (e.g., defensins, bactericidal permeability-increasing protein [BPI],
18
cathepsin G, and proteinase 3, play a role in the passage or “invasion” cationic antimicrobial protein [e.g., CAP37]) and lytic enzymes (e.g.,
of leukocytes through the subendothelial extracellular matrix. Collage- myeloperoxidase, elastase, cathepsin G). 6,21,22 The release of such gran-
nases are particularly important in leukocyte transmigration through ular constituents is accompanied by the generation of reactive oxy-
−
basement membranes. A variety of matrix metalloproteinases, produced gen and nitrogen intermediates (e.g., O , H O , NO), the generation
2
2
2
by several cell types, participate in leukocyte migration, and also play of arachidonate metabolites (e.g., leukotrienes and prostaglandins)
roles in resolution of inflammation and tissue remodeling. Leukocyte and the production of other proinflammatory mediators (see section
emigration and subsequent movement through the interstitium fol- “Regulators of the Inflammatory Response”). 21,22 In some circum-
low chemical concentration gradients; processes facilitated by binding stances these mediators are released into phagolysosomes where they
interactions between leukocyte integrins and complementary sites on contribute to the destruction of engulfed microbes, while in other
extracellular matrix molecules (e.g., fibronectin). A wide variety of circumstances they are secreted into the extracellular milieu where
9

Kaushansky_chapter 19_p0279-0292.indd 283 9/17/15 5:51 PM