title: Expression of the HGF receptor c-met by macrophages in experimental autoimmune encephalomyelitis.
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 TNFalpha, 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 TNFalpha induce c-met through distinct pathways. Furthermore, TNFalpha- 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.
authors: Division of Clinical Immunology, University Hospital Zurich, Moussonstrasse 13, CH-8044 Zürich, Switzerland. martijn.moransard@usz.ch
authors: Martijn
authors: M
authors: Moransard
authors: Mandy
authors: M
authors: Sawitzky
authors: Adriano
authors: A
authors: Fontana
authors: Tobias
authors: T
authors: Suter
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006023:Glycoproteins; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009566:Nitrates / Q000378:metabolism; D009836:Oligodendroglia / Q000502:physiology; D010446:Peptide Fragments; D010587:Phagocytosis / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D006023:Glycoproteins; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D009566:Nitrates; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met