Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination

Journal of Neuroinflammation

Katsuhisa Masaki¹  Yuko Nakamuta¹  Yiwen Cui¹  Koji Shinoda¹  Ryo Yamasaki¹  Hayato Une¹  Hiroo Yamaguchi¹  Ulfa Camelia Indiasari¹  Satoshi Nagata¹  Jun-ichi Kira²  Magdalena Götz³ 

[1] Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan;Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan;Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Ookawa, 831-8501, Fukuoka, Japan;Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, 2-6-11 Yakuin, Chuo-ku, 810-0022, Fukuoka, Japan;Physiological Genomics, Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany;

关键词: Experimental autoimmune encephalomyelitis;    Connexin 43;    Multiple sclerosis;    Microglia;    Astroglia;    Chemokine;    Cytokine;   

DOI  :  10.1186/s12974-021-02176-1

来源: Springer

【 摘 要 】

BackgroundBrain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation.MethodsBecause glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35–55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls.ResultsAcute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls.ConclusionsThe ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.

【 授权许可】

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