Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis.
Although semaphorins were originally identified as axonal guidance molecules during neuronal development, it is emerging that several semaphorins play crucial roles in various phases of immune responses. Sema4D/CD100, a class IV semaphorin, has been shown to be involved in the nervous and immune systems through its receptors plexin-B1 and CD72, respectively. However, the involvement of Sema4D in neuroinflammation still remains unclear. We found that Sema4D promoted inducible NO synthase expression by primary mouse microglia, the effects of which were abolished in plexin-B1-deficient but not in CD72-deficient microglia. In addition, during the development of experimental autoimmune encephalomyelitis (EAE), which was induced by immunization with myelin oligodendrocyte glycoprotein-derived peptides, we observed that the expression of Sema4D and plexin-B1 was induced in infiltrating mononuclear cells and microglia, respectively. Consistent with these expression profiles, when myelin oligodendrocyte glycoprotein-specific T cells derived from wild-type mice were adoptively transferred into plexin-B1-deficient mice or bone marrow chimera mice with plexin-B1-deficient CNS resident cells, the development of EAE was considerably attenuated. Furthermore, blocking Abs against Sema4D significantly inhibited neuroinflammation during EAE development. Collectively, our findings demonstrate the role of Sema4D-plexin-B1 interactions in the activation of microglia and provide their pathologic significance in neuroinflammation.
Okuno
Tatsusada
T
Department of Immunopathology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan.
Nakatsuji
Yuji
Y
Moriya
Masayuki
M
Takamatsu
Hyota
H
Nojima
Satoshi
S
Takegahara
Noriko
N
Toyofuku
Toshihiko
T
Nakagawa
Yukinobu
Y
Kang
Sujin
S
Friedel
Roland H
RH
Sakoda
Saburo
S
Kikutani
Hitoshi
H
Kumanogoh
Atsushi
A
D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011828:Radiation Chimera / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D039961:Semaphorins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; C103150:Sema4d protein, mouse; D039961:Semaphorins