Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 4; pp. 2160 - 2169
• Main Authors: Zhao, Yinan, Yamasaki, Ryo, Yamaguchi, Hiroo, Nagata, Satoshi, Une, Hayato, Cui, Yiwen, Masaki, Katsuhisa, Nakamuta, Yuko, Iinuma, Kyoko, Watanabe, Mitsuru, Matsushita, Takuya, Isobe, Noriko, Kira, Jun-ichi
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.01.2020
• Series: PNAS Plus
• Subjects: Ablation; Astrocytes; Biological Sciences; Carbon tetrachloride; CCL3 protein; CCL4 protein; CCR6 protein; CD3 antigen; CD4 antigen; Chemokines; Connexin 43; CXCR3 protein; Cytokines; Demyelination; DNA microarrays; Experimental allergic encephalomyelitis; Flox; Glycoproteins; Helper cells; Inflammation; Interleukin 1; Interleukin 17; Lymphocytes; Lymphocytes T; Microglia; Monocyte chemoattractant protein 1; Multiple sclerosis; Myelin; Oligodendrocytes; Phenotypes; PNAS Plus; Spinal cord; Tamoxifen; γ-Interferon; connexin 47; astroglia; experimental autoimmune encephalomyelitis; microglia; multiple sclerosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1901294117

In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injury-response phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation.