Combinatorial model of chemokine involvement in glomerular monocyte recruitment: Role of CXC chemokine receptor 2 in infiltration during nephrotoxic nephritis

A sequential model involving chemokines has been proposed for leukocyte ext ravasation into areas of inflammation; however, site-specific aspects remai n to be elucidated. Hence, we studied the role of chemokines produced by me sangial (MC) or glomerular endothelial cells (GEC) and their receptors in g lomerular recruitment of monocytes. Stimulation of MC with TNF-alpha up-reg ulated mRNA and protein of CC and CXC chemokines but not constitutive expre ssion of the CX3C chemokine fractalkine. While growth-related activity (GRO )-alpha was immobilized to MC proteoglycans, monocyte chemotactic protein ( MCP)-1 was secreted into the soluble phase. Firm adhesion and sequestration of monocytes on activated MC was supported by the GRO-alpha receptor CXCR2 and to a lesser extent by CX3CR, whereas the MCP-1 receptor CCR2 contribut ed to their transendothelial chemotaxis toward activated MC. In contrast, f ractalkine mRNA and protein was induced by TNF-alpha in transformed rat GEC , and both CXCR2 and CX3CR mediated monocyte arrest on GEC in shear flow. T he relevance of these mechanisms was confirmed in a rat nephrotoxic nephrit is model where acute glomerular macrophage recruitment was profoundly inhib ited by blocking CXCR2 or CCR2. In conclusion, our results epitomize a comb inatorial model in which chemokines play specialized roles in driving glome rular monocyte recruitment and emphasize an important role for CXCR2 in mac rophage infiltration during early phases of nephrotoxic nephritis.