Expression of the HGF receptor c-met by macrophages in experimental autoimmune encephalomyelitis

✍ Scribed by Martijn Moransard; Mandy Sawitzky; Adriano Fontana; Tobias Suter

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 610 KB
• Volume: 58
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.20945

✦ Synopsis

Abstract

Hepatocyte growth factor (HGF) 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 HGF/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 TNFα, but not IL‐6, IL‐10, or IL‐13, are able to induce c‐met expression in macrophages. In addition, using TNF signaling deficient macrophages we demonstrate that LPS and TNFα induce c‐met through distinct pathways. Furthermore, TNFα‐ 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. © 2009 Wiley‐Liss, Inc.