Expression of the HGF Receptor c-met by Macrophages in Experimental Autoimmune Encephalomyelitis

Hepatocyte growth factor (FIGF) is a pleiotropic cytokine able to evoke a wide array of cellular responses including proliferation, migration, and survival through activation Of its receptor c-met. Various types of leukocytes have been described to express c-met suggesting that HGP/c-met Signaling may directly Influence leukocyte responses in inflammation. We have investigated the HGF/c-met pathway in experimental autoimmune encephalomyelitis (EAE), a common Mouse model of multiple sclerosis (MS), in which macrophages play a dual role, contributing directly to CNS damage at disease Onset but promoting recovery during remission by removing myelin debris Here we show that during EAE both HGF and c-met are expressed in the CNS and that c-met is activated We subsequently demonstrate that. c-met is primarily expressed in inflammatory lesions by macrophages and a small number of dendritic cells (DCs) and oligodendrocyte progenitor cells (OPCS) but not by microglia or T cells Complementary in. vitro experiments show that only LPS and TNR alpha, but not IL-6, IL-10, or IL-13, are able to Induce c-met expression in marophages. In addition. using TNF signaling deficient macrophages we demonstrate that LPS and TNF alpha induce c-met through distinct pathways Furthermore, TNF alpha- and LPS-induced c-met is functional because treatment of macrophages with recombinant HGF results in rapid phosphorylation of c-met Interestingly, HGF/c-met signaling does not modulate cytokine expression, phagocytosis, or antigen presentation but promotes proliferation of activated macrophages Taken together, our data indicate a pro-inflammatory role for the HGF/c-met pathway in EAE rather than a role in the initiation of repair mechanisms. (C) 2009 Wiley-Liss, Inc