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1008 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1009

the presence of LPS and LPS-binding protein to generate proinflam- microbial membrane components are largely present on the cell surface,
matory mediators, and uPAR interaction with CD11b/CD18 mediates and include TLR2 that recognizes lipoproteins and lipopeptides in asso-
neutrophil migration by recruiting and activating the urokinase-type ciation with either TLR1 or TLR6. CD14 is known as an LPS-binding
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plasminogen activator. 29 protein but is not itself able to signal and presents LPS to TLR4. TLR5
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binds flagellin, and TLR11 binds profilin-like proteins of protozoa.
TRANSENDOTHELIAL MIGRATION TLRs that recognize viral components are largely expressed on intra-
cellular vesicles that may fuse with phagosomes and include TLR3 (not
Fully extended and open integrins bind ICAM-1 firmly and thus medi- present in neutrophils) that recognizes double-stranded RNA, TLR7/8
ate attachment of neutrophils to endothelial cells. ICAM-1 and -2 that binds viral single-stranded RNA, and TLR9 that binds unmethy-
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direct the motion of neutrophils to points of egress from the vascular lated GpC regions on DNA. 54
lining. The majority are guided to points where three or more endo- Ligand binding, that is, dimerization of TLRs leads to recruit-
thelial cells join. Intracellular signals from ICAMs loosen the binding ment of one of four intracellular adaptor proteins to the TIR (toll/IL-1
between endothelial cell junctions provided by homotypic interaction receptor) domain of the TLR. These proteins include MyD88 (myeloid
of VE-cadherins. 39 differentiation factor 88), Mal/TIRAP (MyD88-adaptor-like/toll-IL 1
Platelet endothelial cell adhesion molecule 1 (PECAM-1), endo- receptor domain containing adaptor protein), TRAM (TRIF-related
thelial cell-selective adhesion molecule (ESAM), junctional adhesion adaptor molecule), and TRIF (TIR domain-containing adaptor induc-
molecule A, B, and C (JAMs), and CD99 also form homotypic interac- ing IFN-β). While many TLRs (5, 7, 8, and 9) exclusively use MyD88,
tions between endothelial cells; however, neutrophils also express these TLR2 requires both Mal and MyD88 and TLR4 can use either Mal
adhesion proteins and may displace the interendothelial cell homotypic (MyD88-adaptor-like) and MyD88 or TRAM and TRIF to signal to
binding with neutrophil–endothelial cell binding mediated by the same NF-κB (nuclear factor-κB) or interferon regulatory factor (IRF)-3. 55,56,47
proteins. In this way neutrophils can “zipper” through 40–42 and exit by CLRs comprise a heterogeneous group of trans-membrane recep-
this paracellular route. A minority of neutrophils exit by a transcellular tors that bind carbohydrates such as mannose, fucose, and β-glucans
route through so-called endothelial cups. 42 present on a variety of microbes, fungi in particular. They signal largely
Pericytes are perivascular contractile cells that interact with endo- via their cytosolic ITAMs and Syk to activate NF-κB, nuclear factor of
thelial cells and regulate vascular permeability. Neutrophils exit the vas- activated T cell (NFAT), and microtubule-associated protein kinases
cular wall through gaps between pericytes. Pericytes adopt different (MAPKs) resulting in production of proinflammatory cytokines. 48
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morphologies and distributions in different tissues. Such may explain NLR proteins are cytosolic proteins that are divided into five sub-
differences in neutrophil recruitment to viscera. 44 families, NLRA, NLRB, NLRC, NLRP, and NLRX. Their N terminus
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Once out in tissues the forefront neutrophils generate IL-8 and contains either a caspase activation and recruitment domain (CARD) or
LTB in order to recruit an additional swarm of neutrophils to the area a pyrin domain (PYD). The NLRC members NOD1 and NOD2 recog-
4
and recruit later incoming monocytes and macrophages. 45 nize peptidoglycans of both Gram-positive and Gram-negative bacteria
and signal to activate the NF-κB pathway. Other members of the NLRC
and NLRP subfamily are essential in organizing the inflammasome.
NEUTROPHIL SURFACE PROTEINS The NLRs multimerize through their CARDs into inflammasomes,
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Several proteins associated with the surface of the neutrophil function cytoplasmic structures that activate caspase-1, which, in turn, convert
+
+
in the normal housekeeping activities such as Na /K adenosine triphos- pro–IL-1 and pro–IL-18 to the mature proinflammatory cytokines that
phatase (ATPase), but others serve specific functions such as L-selectin, are secreted. 57
PSGL-1, and integrins. The surface of neutrophils is highly dynamic as A variety of chemokine receptors are found on the surface of the
a result of the incorporation of membrane from intracellular vesicles neutrophil. These are in general G-protein–coupled receptors. Other
and granules, a process that is known to add significantly to the total G-protein–coupled receptors on neutrophils are the purine receptors
cell surface measured by an increase in electric capacitance. A number for adenosine diphosphate (ADP) and ATP, the PAF receptor C5a,
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of membrane-bound receptors are localized to secretory vesicles and and formyl-methionyl-leucyl-phenylalanine (fMLP) receptors. Recep-
incorporated into the surface membrane when secretory vesicles fuse tors not belonging to the G-protein–coupled receptor family include
with the plasma membrane, as occurs during diapedesis. This enhances receptors for IL-1, IL-10, and TNF-α, and the growth factors recep-
the ability of neutrophils to respond to the signals presented by endo- tors for granulocyte colony-stimulating factor (G-CSF) and granulo-
thelial cells or present in the extravascular tissue. cyte-macrophage colony-stimulating factor (GM-CSF). Both growth
factor receptors are important for myeloid development, and play an
Receptors for Recognition of Microbes important role in enhancing neutrophil function and gene transcription
Neutrophils and other cells of the innate immune system recognize in mature neutrophils. A burst of transcriptional activity is associated
microbes through germline-encoded receptors, which recognize molec- with the diapedesis of neutrophils into tissues, which results in down-
ular patterns that are relative unique to pathogens and shared among regulation of proapoptotic genes and upregulation of genes coding for
groups of pathogens, so-called pathogen-associated molecular patterns antiapoptotic proteins, upregulation of genes encoding chemokines and
(PAMPs). These pattern-recognition receptors (PRRs) include the cytokines that may recruit macrophages, T cells and additional neu-
membrane-bound toll-like receptors (TLRs) and C-type lectin recep- trophils, and downregulation of genes encoding chemokine receptors
tors (CLRs), and the cytosolic nucleotide-binding oligomerization (see Fig. 66–2). 58
domain (NOD)-like receptors (NLRs) and RIG-like receptors (RLRs). 47–
50 Although PRRs are highly expressed in myeloid cells, they are also Surface Components for Phagocytosis
widely expressed in cells that are regularly exposed to microorganisms, Neutrophils express the Fc α receptor (CD89) for immunoglobu-
particularly in epithelial cells. lin (Ig) A and IgG receptors, FcγRIIA (CD32), and FcγRIII (CD16).
TLRs are type 1 transmembrane signaling receptors that are acti- Neutrophils also express receptors for the complement components,
vated by dimerization induced by ligand binding. The TLRs may including CD1qR, CR1 (CD35), CR3 (CD11/CD18), and CR4. CR1
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dimerize both as homodimers and heterodimers. TLRs that recognize binds CD3b, C4b, and C3bi with decreasing affinity. CR3 recognizes

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