title: Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury.
abstract: BACKGROUND
  A unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. Reactive astrocytes line the spinal cavity, walling off the lesion core from the normal spinal tissue, and are thought to play multiple important roles in SCI. The contribution of cell death, particularly the apoptosis of neurons and oligodendrocytes during the process of cavitation has been extensively studied. However, how reactive astrocytes are eliminated following SCI remains largely unclear.
  
  
  RESULTS
  By immunohistochemistry, in vivo propidium iodide (PI)-labeling and electron microscopic examination, here we reported that in mice, reactive astrocytes died by receptor-interacting protein 3 and mixed lineage kinase domain-like protein (RIP3/MLKL) mediated necroptosis, rather than apoptosis or autophagy. Inhibiting receptor-interacting protein 1 (RIP1) or depleting RIP3 not only significantly attenuated astrocyte death but also rescued the neurotrophic function of astrocytes. The astrocytic expression of necroptotic markers followed the polarization of M1 microglia/macrophages after SCI. Depleting M1 microglia/macrophages or transplantation of M1 macrophages could significantly reduce or increase the necroptosis of astrocytes. Further, the inflammatory responsive genes Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) are induced in necroptotic astrocytes. In vitro antagonizing MyD88 in astrocytes could significantly alleviate the M1 microglia/macrophages-induced cell death. Finally, our data showed that in human, necroptotic markers and TLR4/MyD88 were co-expressed in astrocytes of injured, but not normal spinal cord.
  
  
  CONCLUSIONS
  Taken together, these results reveal that after SCI, reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis, partially through TLR/MyD88 signaling, and suggest that inhibiting astrocytic necroptosis may be beneficial for preventing secondary SCI.
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
authors: Hong
authors: H
authors: Fan
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
authors: Kun
authors: K
authors: Zhang
authors: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xin Si Road, Xi'an, Shaanxi, 710038, China.
authors: Lequn
authors: L
authors: Shan
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
authors: Fang
authors: F
authors: Kuang
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
authors: Kun
authors: K
authors: Chen
authors: Zhejiang University China Brain Bank, Department of Pathology and Pathophysiology, Department of Neuroscience, 866 Yu-Hang-Tang Road, Zhejiang University Zi-Jin-Gang Campus, Hangzhou, Zhejiang, 310058, China.
authors: Keqing
authors: K
authors: Zhu
authors: Department of Physiology & Department of Pathophysiology, School of Basic Medical Sciences, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, Shaanxi, 710032, China.
authors: Heng
authors: H
authors: Ma
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. jugong@fmmu.edu.cn.
authors: Gong
authors: G
authors: Ju
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. yazhouw@fmmu.edu.cn.
authors: Ya-Zhou
authors: YZ
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4