Endogenous modulators of inflammatory cell recruitment

Abstract

Leukocyte recruitment is a central immune process. Multiple factors have been described to promote leukocyte infiltration into inflamed tissues, but only recently has evidence for endogenous negative modulators of this inflammatory process emerged. The discovery of several locally produced modulators has emerged into a new field of endogenous inhibitors of leukocyte extravasation. Recent findings from several inflammatory disease models show that tissues can self-regulate the recruitment of inflammatory cells, suggesting that local tissues may have a greater 'regulatory say' over the immune response than previously appreciated. Here, we propose that locally produced modulators of leukocyte recruitment may represent local homeostatic mechanisms that tissues and organs may have evolved for protection against the destructive potential of the immune system.

Figure 1. Endogenous modulators of leukocyte recruitment

(a) Leukocyte-derived PTX-3 binds to endothelial P-selectin thereby inhibiting the PSGL-1/P-selectin–dependent rolling. (b) GDF-15 counteracts the chemokine-induced activation of β2-integrins by targeting both affinity (involving conformational changes in a single integrin receptor resulting in higher binding to its ligand) and valency (involving the clustering of more integrin receptors). The inhibitory action of GDF-15 on integrin activation is mediated via upregulation of Cdc42-GTPase activity that antagonizes the activity of Rap1-GTPase. (c) Finally, endothelial cell-associated Del-1 inhibits LFA-1-dependent leukocyte adhesion. The adhesive interactions between LFA-1 on leukocytes and ICAM-1 on endothelial cells constitute a major mechanism mediating firm leukocyte arrest on the endothelium and the subsequent transmigration process.