TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway.
In acute experimental autoimmune encephalomyelitis (EAE), demyelination is induced by myelin-specific CD4(+) T lymphocytes and myelin-specific antibodies. Recovery from the disease is initiated by cytokines which suppress T cell expansion and the production of myelin-toxic molecules by macrophages. Th2/3 cell-derived signals may also be involved in central nervous system (CNS) repair. Remyelination is thought to be initiated by the recruitment and differentiation of oligodendrocyte precursor cells (OPC) in demyelinated CNS lesions. Here, we report that unlike Th1 cytokines (TNF-alpha, IFN-gamma), the Th2/3 cytokine TGF-beta induces primary microglia from C57BL/6 mice to secrete a chemotactic factor for primary OPC. We identified this factor to be the hepatocyte growth factor (HGF). Our studies show that TGF-beta-1-2-3 as well as IFN-beta induce HGF secretion by microglia and that antibodies to the HGF receptor c-Met abrogate OPC chemotaxis induced by TGF-beta2-treated microglia. In addition we show spinal cord lesions in EAE induced in SJL/J mice to contain both OPC and HGF producing macrophages in the recovery phase, but not in the acute stage of disease. Taken these findings, TGF-beta may play a pivotal role in remyelination by inducing microglia to release HGF which is both a chemotactic and differentiation factor for OPC.
Lalive
Patrice H
PH
Section of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland.
Paglinawan
Rey
R
Biollaz
Gregoire
G
Kappos
Elisabeth A
EA
Leone
Dino P
DP
Malipiero
Ursula
U
Relvas
Joao B
JB
Moransard
Martijn
M
Suter
Tobias
T
Fontana
Adriano
A
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002633:Chemotaxis / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000276:immunology; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology; D012075:Remission, Spontaneous; D013118:Spinal Cord Diseases / Q000276:immunology / Q000473:pathology; D013234:Stem Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology*
D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met