title: MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination.
abstract: The major challenge for progressive multiple sclerosis therapy is the promotion of remyelination from inflammation-induced demyelination. A switch from an M1- to an M2-dominant polarization of microglia is critical in these repair processes. In this study, we identified the homeobox gene msh-like homeobox-3 (Msx3) as a new pivotal regulator for microglial polarization. MSX3 was induced during microglia M2 polarization and repressed in M1 cells. The expression of MSX3 in microglia was dynamically regulated during experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. The overexpression of MSX3 in microglia promoted M2 but impeded M1 polarization. Interrupting MSX3 expression in microglia accelerated inflammation-induced demyelination and neurodegeneration. The conditioned medium from MSX3-transduced microglia promoted oligodendrocyte progenitor survival, differentiation, and neurite outgrowth. The adoptive transfer of MSX3-transduced microglia suppressed EAE and facilitated remyelination within the murine CNS in EAE and the LPC model. Mechanically, chromatin immunoprecipitation assays also indicated that MSX3 directly regulated three key genes associated with microglia M2 polarization, including Pparg, Stat6, and Jak3. Importantly, we found that overexpression of MSX3 in human-derived microglia represents the M2 phenotype and ameliorated EAE after intraventricular injection. Our findings suggest a new homeobox protein-dependent mechanism for driving microglia M2 polarization and identify MSX3 as an attractive therapeutic approach for preventing inflammation-induced demyelination and promoting remyelination.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhongwang
authors.identifier: http://orcid.org/0000-0002-8212-0158
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Dingya
authors.identifier: http://orcid.org/0000-0002-6583-4503
authors.initials: D
authors.lastname: Sun
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Tan
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Fang
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yingyan
authors.initials: Y
authors.lastname: Pu
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Huang
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China caoli.smmu@gmail.com chenghe@smmu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of the Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China caoli.smmu@gmail.com chenghe@smmu.edu.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016764:Cell Polarity; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D053616:Janus Kinase 3 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000378:metabolism*; D009186:Myelin Sheath / Q000502:physiology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control; D016501:Neurites / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; C104294:Msx3 protein, mouse; D047495:PPAR gamma; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3
keywords: EAE; MSX3; microglia; multiple sclerosis; polarization