MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination

Journal of Neuroscience - Tập 35 Số 16 - Trang 6350-6365 - 2015
Zhongwang Yu1, Dingya Sun1, Jifeng Feng1, Weixing Tan1, Fang Xue1, Ming Zhao1, Xiaolin Zhao1, Yingyan Pu1, Aijun Huang1, Zhenghua Xiang1, Li Cao1, Cheng He1
1Institute 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.

Tóm tắt

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, includingPparg,Stat6, andJak3. 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.

Từ khóa


Tài liệu tham khảo

10.1126/science.1103709

10.1093/brain/123.6.1174

10.1172/JCI26836

10.1016/0896-6273(93)90173-O

10.1161/CIRCRESAHA.110.216523

10.1093/nar/20.17.4465

10.1038/nn.3332

10.1126/science.1194637

10.1016/j.neuroscience.2008.07.062

10.1038/22572

10.1152/physrev.00011.2010

10.1523/JNEUROSCI.3257-09.2009

10.1093/brain/awn096

10.1038/nri3088

10.1016/j.expneurol.2012.06.011

10.1242/dev.00994

10.1182/blood-2008-03-148726

10.1523/JNEUROSCI.0710-14.2014

10.1146/annurev.immunol.021908.132532

10.1182/blood-2012-06-436212

Mason, 2003, Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination, J Neurosci, 23, 7710, 10.1523/JNEUROSCI.23-20-07710.2003

10.1023/B:MCBI.0000049353.38098.51

10.1083/jcb.121.6.1397

10.1042/bj3530013

10.1097/01.wco.0000169752.54191.97

10.1038/nn.3469

10.1111/imm.12163

10.1523/JNEUROSCI.1922-07.2007

10.1038/nm.2266

10.1093/brain/awm219

10.1016/j.stem.2011.11.019

10.1073/pnas.0908641106

10.1093/brain/121.12.2221

10.1038/nn.2172

10.1016/0925-4773(96)00505-9

10.1016/j.immuni.2010.11.009

10.1146/annurev.neuro.30.051606.094313

10.1016/S0925-4773(96)00562-X

10.1371/journal.pone.0009956

10.1016/S0896-6273(03)00326-X