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138 Part II Cellular Basis of Hematology

the most relevant group of proteases implicated in the shedding of interactions in high endothelial venules (HEVs) in lymph nodes
L-selectin, VCAM, as well as CX3CL1 and junctional adhesion mol- (LNs) and Peyer patches (PPs), but unlike control cells, the PTX-
ecule (JAM)-A, and thereby involved in facilitating the detachment treated cells are unable to undergo integrin-dependent firm arrest.
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of leukocytes. In addition, chemokines such as CCL2, CXCL10, Chemokine receptor activation precipitates a cascade of intracellular
and CXCL12 are cleaved and inactivated by MMP-2 and MMP- signaling and adapter proteins, including Kindlin-3 and RAP-RAPL,
9. 56,57 Apart from MMPs, proteases stored in neutrophil granules, which are involved in the so-called inside-out signaling that results in
in particular cathepsin G and elastase, inactivate chemokines such integrin activation. Modifications at the cytoplasmic tails of the
as CXCL12 and its receptor CXCR4 that regulate not only the integrin α and β chains are critical to regulate leukocyte adhesion to
migration of mature leukocytes but also the mobilization and integrin ligands, such as the binding and spreading of neutrophils on
homing of immature HSCs. 58,59 Hence, proteases by means of their intercellular cell adhesion molecule (ICAM)-1 and the complement
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chemokine-modifying properties must be regarded as integral com- C3 activation product, iC3b. Once arrested, the adherent leukocytes
ponents in the control of trafficking of mature leukocytes and their rapidly polarize and slowly migrate within the vessel in random
precursors. directions. 69–71 The intraluminal crawling is thought to be essential
In general, leukocyte trafficking can be classified into three distinct to enable leukocytes to find exit points within the vessel through
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patterns of migration (1) entry into tissues from the circulation; (2) which they can leave the vasculature. A subset of monocytes crawl
migration within tissues; and (3) exit from tissues. The following within uninflamed microvessels under steady-state conditions. 62,72,73
sections will discuss each of these steps in leukocyte trafficking. These patrolling monocytes are poised to provide immune surveil-
lance of the endothelial cell surfaces and clear the intravascular
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debris, but may also enter the extravascular space in response to
LEUKOCYTE ENTRY INTO TISSUES damage and infection. Once emigrated, some monocyte cells may
differentiate into macrophages or dendritic cells (DCs). In some
In order to leave the circulation and enter target tissues, leukocytes tissues and organs, such as the intestine, monocyte emigration con-
must engage in several sequential steps of adhesion to the endothelial tributes throughout life to the replenishing of the resident macrophage
cells, which most often take place in the venular segment of the pool. 72,74,75 In other tissues, macrophage and DC precursors home
circulatory tree. 27,60–65 Discrete individual adhesion steps are mediated only during the embryonic period from either the liver or yolk sack,
by binding interactions of pairs of adhesion receptors and their and the resident mature cells proliferate in situ to give rise to their
counter-ligands expressed in trans-geometry by leukocytes and progeny. 76,77
endothelial cells. The initial tethering of leukocytes to the endothelial The interactions between the β2-integrins LFA-1 and Mac-1 with
cell is induced by adhesion molecules, which are able to rapidly bind endothelial ICAMs are required for intravascular adhesion and crawl-
their ligands with high tensile strength. The most important initiators ing. However, the specificity of these interactions differs between
of leukocyte tethering are selectins, expressed on leukocytes different leukocytes, such as neutrophils and monocytes. 69,72 Neutro-
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(L-selectin), endothelial cells (E- and P-selectin), and platelets phil luminal crawling is mainly mediated by Mac-1, whereas
(P-selectin). The most important selectin counter-ligands are sialo- monocytes and T cells use LFA-1. 1,72 Recent studies using blocking
mucins, which are decorated with oligosaccharides related to sialyl- antibodies against Mac-1 and LFA-1 showed that crawling patterns
x
Lewis , including P-selectin glycoprotein ligand (PSGL)-1 and the of monocytes and neutrophils differ at steady state compared with
peripheral-node addressin (PNAd). Selectin-mediated adhesion those under inflammatory conditions; both LFA-1 and Mac-1 con-
bonds that are formed in the bloodstream are transient and do not tribute to monocyte crawling; however, the LFA-1–dependent crawl-
allow prolonged, firm leukocyte arrest. As tethered leukocytes are ing in unstimulated venules becomes Mac-1 dependent upon
pushed along the vessel wall by the blood flow, selectin bonds con- inflammation. By contrast, Mac-1 alone is responsible for neutrophil
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tinuously dissociate at the upstream end of the cells and new ones crawling in both unstimulated and cytokine-stimulated venules.
form downstream, resulting in the slow rolling motion characteristic This indicates that differences in monocyte and neutrophil crawling
of leukocyte tethering. To undergo firm adhesion the rolling leukocyte behavior result from involvement of different β2 integrins and con-
must engage additional adhesion receptors that belong to the integrin sequently affect the next step of the leukocyte migration cascade:
family, particularly CD11a/CD18 (leukocyte function–associated transendothelial migration.
antigen-1 [LFA-1]) and the α4 integrins, α4β1 (very late antigen Transendothelial migration or diapedesis is a critical event allow-
[VLA]-4) and α4β7. Without exception, individual integrins are ing leukocytes to cross the vascular wall and enter their target tissue.
expressed by the subsets of leukocytes and their counter-ligands by Two routes of leukocyte diapedesis have been observed: a paracellular
the endothelial cells. route that dominates most extravasation processes, and a transcellular
Whereas selectins are constitutively active, integrins first need to route reported for neutrophils and some T cells. 79–85 Both routes
be activated to assume a high-affinity state that promotes efficient involve the action of apical and junctional endothelial ICAM-1, and,
adhesion to endothelial ligands. Integrin activation is induced by at least in some settings, vascular cell adhesion molecule-1 (VCAM-
chemoattractant signals that trigger a reversible change in integrin 1). In inflammatory conditions, additional junctional endothelial
conformation (leading to enhanced ligand-binding affinity) or in ligands such as PECAM-1, vascular endothelial (VE)-cadherin,
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integrin clustering (enhancing avidity), or both. Some (but not all) ESAM, CD99, CD99L2, and junctional adhesion molecule (JAMs)
chemokines presented on the luminal surface of microvascular can contribute to leukocyte diapedesis. 80,86–92
endothelial cells can trigger rapid integrin activation and efficiently After penetration of the endothelial barrier, leukocytes may move
induce leukocyte arrest. The retention of chemokines on the vessel further within the interstitium toward their target destinations in the
endothelium is mediated through binding to glycosaminoglycans tissue. This locomotion is considered to reflect in vivo chemotaxis,
(GAGs) in the luminal glycocalix. Chemokines that are produced in increased rate-directed cell locomotion driven by the putative gradi-
the extravascular space can be transported across the endothelial ents of chemotattractants. 93,94 Several signaling pathways have been
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barrier to the luminal surface. This process is triggered by chemo- proposed to be involved in this gradient-driven process, the most
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kine binding to the atypical chemokine receptor ACKR1 (previously predominant being the PI3K pathway. Thereby, leukocytes use an
known as Duffy antigen receptor for chemokines [DARC]), which is “internal compass” for sensing the direction of chemotactic gradients,
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also involved in luminal immobilization of chemokines. ACKR1 and undergo polarization characterized by the formation of lamelli-
expression by the endothelial cells characterizes only the venular but podia at the leading edge of the cell and an uropod at the trailing
not the capillary or arterial segment of the circulatory tree. 67 edge. 95,96 Chemokines released by a broad range of tissue cells, epi-
Chemokines signal through the Gα i subfamily of large heterotri- thelial cells, stromal cells, mast cells, smooth muscle cells, fibroblasts,
meric G proteins, which can be inhibited by pertussis toxin (PTX). myocytes, and tissue-resident immune cells may form gradients and
Consequently, intravital microscopy studies have shown that lympho- mediate the leukocyte chemotaxis in the interstitium. In this context,
cytes treated with PTX undergo normal tethering and rolling the spatiotemporal formation of chemokine gradients in the