Firm Adhesion

It is thought that most if not all leukocytes adhere only after having rolled. Several studies suggest that direct adhesion (from the free-flowing leukocyte pool) is extremely rare. E-selectin participates in the conversion of rolling to firm adhesion. E-selectin deficient mice have a reduced number of firmly adherent leukocytes in response to local chemoattractant (Ley et al., 1998) or cytokine stimulation (Milstone et al., 1998). This defect may be related to the more rapid rolling velocities in the absence of E-selectin (Kunkel and Ley, 1996).

Interfering with CD18 integrin function is one of the most efficient ways to curb leukocyte recruitment in many forms of experimental inflammation. Although the response to exogenous chemoattractant is drastically reduced when CD18 is absent or not functional ( Scharffetter-Kochanek et al., 1998; Arfors et al., 1987), cytokine treatment still yields a robust inflammatory response in gene-targeted mice lacking CD18 (Jung et al., 1998). This suggests that CD18 integrins participate in leukocyte arrest, but are not always required. Neutrophils express small amounts of other integrins, including VLA-4 (41 integrin) (Kubes et al., 1995), which may be important in these alternative pathways. However, CD18 deficient mice have severe inflammatory defects including skin ulcerations, elevated neutrophil counts and immunoglobulin levels, increased susceptibility to streptococcus pneumoniae, and a severe defect in leukocyte adhesion and T-cell activation (Scharffetter-Kochanek et al., 1998), a defect in leukocyte recruitment to peritonitis (Walzog et al., 1999) and a lack of neutrophil recruitment to the skin (Mizgerd et al., 1997). Patients lacking CD18 expression suffer from leukocyte adhesion deficiency type 1 (LAD-1). When CD18 is totally absent, LAD-1 is a very severe disease, which can lead to early lethality (Anderson and Springer, 1987).

Among the 2 integrins, only LFA-1 and Mac-1 have been investigated in vivo. Intravital microscopic studies suggest that LFA-1 is the most important 2 integrin in firm leukocyte adhesion (Schmits et al., 1996), while Mac-1 has no apparent role in adhesion, but seems to be important in neutrophil activation and phagocytosis (Lu et al., 1997). Nothing is known about the role of the x (p150,95) and d chains (CD11c and CD11d) in leukocyte adhesion or recruitment in vivo.

In cytokine-induced inflammation, slow-rolling leukocytes do not stop abruptly, but show a gradual decrease of their rolling velocity before becoming adherent (Kunkel et al., 2000). This deceleration is strictly dependent on CD18 integrins (Kunkel et al., 2000). Since rolling leukocytes show a graded elevation of intracellular free calcium while rolling more and more slowly, it appears that rolling leukocytes are partially activated before arrest. This process appears to take about one minute or more. Although IL-8 receptor is known to be involved, signaling through adhesion receptors, for example L-selectin (Steeber et al., 1997), may also contribute to this process of physiological leukocyte recruitment.

LFA-1 and Mac-1 both can bind to ICAM-1 and ICAM-2 (Xie et al., 1995; Diamond et al., 1990; Staunton et al., 1989; Dustin and Springer, 1988). A role for ICAM-2 in leukocyte recruitment has not been demonstrated so far. ICAM-2 deficient mice show a prolonged eosinophilic infiltrate in a model of allergic lung inflammation, but have no inflammatory defect (Gerwin et al., 1999). ICAM-1 have a mild inflammatory defect (Sligh, Jr. et al., 1993), not comparable with that seen in CD18 deficient mice. Although it has been argued that alternatively spliced forms of ICAM-1 found in these mice (King et al., 1995) may allow for residual leukocyte binding, these isoforms are only found in thymus and spleen and not in inflamed organs. Recently, an ICAM-1 null mouse has been produced (R.G. Collins and A.L. Beaudet, unpublished information) that should bring definitive answers with respect to the role of ICAM-1 in inflammation. Leukocytes rolling in resting inflamed venules require ICAM-1 to stop in response to a chemoattractant (Argenbright et al., 1991). However, ICAM-1 is no longer required after activation with inflammatory cytokines (Foy and Ley, 1999; Ley et al., 1998), suggesting that other, unknown endothelial ligands for 2 integrins must exist.

Monocytes, eosinophils, and many lymphocytes express 41 integrin (VLA-4) (Hynes, 1992), and mouse and rat neutrophils also express small amounts (Kubes et al., 1995). When other adhesion molecules are unavailable, 41 integrin can mediate both leukocyte rolling (Berlin et al., 1995; Sriramarao et al., 1994; Alon et al., 1995) and firm adhesion. 41 integrin binds to endothelial VCAM-1 (Luscinskas et al., 1995) and alternatively spliced fibronectin (Guan and Hynes, 1990). Intravital microscopic evidence available to-date suggests that most 4-dependent binding is through VCAM-1, because antibodies to VCAM-1 applied in the microcirculation (U. Jung and K. Ley, unpublished observations) and in atherosclerotic arteries (Ramos et al., 1999) block leukocyte rolling and adhesion to a similar extent as 4 antibodies. Since homozygous α4 (Yang et al., 1995) or VCAM-1 (Gurtner et al., 1995) deficient mice die before birth due to morphogenetic failure unrelated to the inflammatory function of these molecules, definitive answers for the roles of these two adhesion molecules await the generation of tissue-specific and/or inducible null mutants.

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