Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

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.

Regulation of immune cell responses by semaphorins and their receptors

“…Sema4D-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) due to impaired antigen-specific T-cell responses in the draining lymph nodes and attenuated inflammation in the central nervous system. 51 In addition, T-cell-derived Sema4D has been implicated in the collapse of process extension of immature oligodendrocytes and the death of immature neural cells in the spinal cords of patients with human T-cell lymphotropic virus type 1-associated myelopathy 52 ( Table 1). Figure 1 Representative immune semaphorins and their receptors in lymphoid and non-lymphoid cells.…”

Analysis of the Impact of CD200 on Neurodegenerative Diseases

“…Humoral activation of microglia, involving the complement system has also been described as a consequence of its interaction with plexin B1 (Chabbert-de Ponnat et al, 2005). However, in complete contrast to these findings, a Sema4D fusion protein has been reported to increase NO production in microglia and this was abolished in cells prepared from plexin B1-deficient mice (Okuno et al, 2010). The possible role of SEMA4D as a regulator of microglial function requires further examination.…”

The CNS Innate Immune System and the Emerging Roles of the Neuroimmune Regulators (NIRegs) in Response to Infection, Neoplasia and Neurodegeneration

“…In the CNS microglia are activated by Sema 4D binding to plexin B1, rather than the CD72 molecule that is also expressed by microglia (Okuno et al;2009) Interestingly, plexin B1 and Sema 4D deficient mice are resistant to EAE induced by MOG derived peptide, because of the failure to generate MOG -specific T cells, emphasising the importance of functional Sema 4D for T cell activation and differentiation within the CNS (Takegahara et al, 2005). Antibodies raised against Sema 4D reduced inflammation during EAE, this was explained as the result of blocking T cells expressing Sema 4D interacting with microglial plexin to promote expression of pro inflammatory cytokines (Okuno et al, 2009).…”