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Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination
- Source :
- Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-19 (2021), Journal of Neuroinflammation
- Publication Year :
- 2021
- Publisher :
- BMC, 2021.
-
Abstract
- Background Brain 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. Methods Because 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. Results Acute 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. Conclusions The 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.
- Subjects :
- medicine.medical_specialty
Encephalomyelitis, Autoimmune, Experimental
Immunology
Gene Expression
Proinflammatory cytokine
Multiple sclerosis
Cellular and Molecular Neuroscience
Mice
Astroglia
Internal medicine
medicine
Glutamate aspartate transporter
Animals
Gray Matter
RC346-429
Cytokine
Neuroinflammation
Mice, Knockout
Experimental autoimmune encephalomyelitis
biology
Microglia
Chemistry
General Neuroscience
Research
medicine.disease
Spinal cord
Disease Models, Animal
medicine.anatomical_structure
Endocrinology
Neurology
Spinal Cord
nervous system
Chemokine
Astrocytes
Connexin 43
Neuroinflammatory Diseases
biology.protein
cardiovascular system
Cytokines
sense organs
Neurology. Diseases of the nervous system
Brain Gray Matter
Chemokines
biological phenomena, cell phenomena, and immunity
Demyelinating Diseases
Subjects
Details
- Language :
- English
- ISSN :
- 17422094
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroinflammation
- Accession number :
- edsair.doi.dedup.....1bdcba6b314713f271b8529a15040c60