TY - JOUR
T1 - Connexin 30 deficiency attenuates chronic but not acute phases of experimental autoimmune encephalomyelitis through induction of neuroprotective microglia
AU - Fang, Mei
AU - Yamasaki, Ryo
AU - Li, Guangrui
AU - Masaki, Katsuhisa
AU - Yamaguchi, Hiroo
AU - Fujita, Atsushi
AU - Isobe, Noriko
AU - Kira, Jun-Ichi
N1 - Funding Information:
This work was supported in part by Glial Assembly Grants-in-Aid for Scientific Research on Innovative Areas (MEXT KAKENHI Grant Numbers 25117001 and 25117012) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid for Scientific Research (A) (JSPS KAKENHI Grant Number 16H02657) from the Japan Society for the Promotion of Science. We appreciate the technical assistance of The Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. We thank Ann Turnley, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Publisher Copyright:
Copyright © 2018 Fang, Yamasaki, Li, Masaki, Yamaguchi, Fujita, Isobe and Kira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
PY - 2018/11/7
Y1 - 2018/11/7
N2 - Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.
AB - Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.
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U2 - 10.3389/fimmu.2018.02588
DO - 10.3389/fimmu.2018.02588
M3 - Article
C2 - 30464764
AN - SCOPUS:85056345768
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - NOV
M1 - 2588
ER -