TY - JOUR
T1 - Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis
AU - Zhao, Yinan
AU - Yamasaki, Ryo
AU - Yamaguchi, Hiroo
AU - Nagata, Satoshi
AU - Une, Hayato
AU - Cui, Yiwen
AU - Masaki, Katsuhisa
AU - Nakamuta, Yuko
AU - Iinuma, Kyoko
AU - Watanabe, Mitsuru
AU - Matsushita, Takuya
AU - Isobe, Noriko
AU - Kira, Jun-Ichi
N1 - Funding Information:
ACKNOWLEDGMENTS. This study was supported, in part, by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (J.-i.K.); Japan Society for the Promotion of Science (JSPS) KAKENHI Grants-in-Aid for Scientific Research (A)
Funding Information:
Author contributions: Y.Z., R.Y., H.Y., H.U., K.M., M.W., T.M., N.I., and J.-i.K. designed research; Y.Z., R.Y., H.Y., S.N., H.U., Y.C., K.M., Y.N., K.I., M.W., T.M., N.I., and J.-i.K. performed research; H.Y. and H.U. contributed new reagents/analytic tools; Y.Z., R.Y., H.Y., H.U., Y.C., K.M., K.I., M.W., T.M., N.I., and J.-i.K. analyzed data; Y.Z., R.Y., H.Y., K.I., M.W., T.M., and J.-i.K. wrote the paper; and S.N. and Y.N. performed experiments for revision. Competing interest statement: R.Y. has received honoraria from Biogen Japan; N.I. has received grant support from Mitsubishi Tanabe Pharma, Bayer Yakuhin Ltd., and Japan Blood Products Organization. J.-i.K. is a consultant for Biogen Japan and Medical Review, and has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobel-pharma, Otsuka Pharmaceutical, Sanofi K.K., Chugai Pharmaceutical Co. Ltd., Teijin Pharma, Novartis Pharma, and Medical Review. The remaining authors declare no conflicts of interest. This article is a PNAS Direct Submission.
Funding Information:
(Grant 16H02657) (J.-i.K.), (C) (Grant 16K09694) (R.Y.), and (C) (Grant 26461295) (K.M.) from the Japan Society for the Promotion of Science. The authors gratefully acknowledge financial support from the China Scholarship Council.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/1/28
Y1 - 2020/1/28
N2 - 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 injuryresponse 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.
AB - 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 injuryresponse 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.
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U2 - 10.1073/pnas.1901294117
DO - 10.1073/pnas.1901294117
M3 - Article
C2 - 31932428
AN - SCOPUS:85078684942
SN - 0027-8424
VL - 117
SP - 2160
EP - 2169
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -