D-dopachrome tautomerase activates COX2/PGE2 pathway of astrocytes to mediate inflammation following spinal cord injury

Journal of Neuroinflammation

Aihong Li¹  Zhenjie Zhu²  Yuming Hu²  Yue Zhou²  Aisong Guo²  Chen Chen²  Yingjie Wang³  Huifei Hao³  Hui Li³  Chunshuai Sun³  Yongjun Wang³  Bingqiang He³  Ting Yang³  Xingyuan Zhang³  Huiyuan Ji⁴  Yuxin Zhang⁵ 

[1] Department of Neurology, Affiliated Hospital of Nantong University, 226001, Nantong, People’s Republic of China;Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, 226001, Nantong, People’s Republic of China;Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 226001, Nantong, People’s Republic of China;Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 226001, Nantong, People’s Republic of China;Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, 226001, Nantong, People’s Republic of China;Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 226001, Nantong, People’s Republic of China;Department of Rehabilitation Medicine, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Huangpu District, 200011, Shanghai, People’s Republic of China;

关键词: D-DT;    MIF;    Spinal cord;    Astrocyte;    Inflammation;    PGE;    Injury;    Central nervous system;    COX2;    CD74;   

DOI  :  10.1186/s12974-021-02186-z

来源: Springer

【 摘 要 】

BackgroundAstrocytes are the predominant glial cell type in the central nervous system (CNS) that can secrete various cytokines and chemokines mediating neuropathology in response to danger signals. D-dopachrome tautomerase (D-DT), a newly described cytokine and a close homolog of macrophage migration inhibitory factor (MIF) protein, has been revealed to share an overlapping function with MIF in some ways. However, its cellular distribution pattern and mediated astrocyte neuropathological function in the CNS remain unclear.MethodsA contusion model of the rat spinal cord was established. The protein levels of D-DT and PGE2 synthesis-related proteinase were assayed by Western blot and immunohistochemistry. Primary astrocytes were stimulated by different concentrations of D-DT in the presence or absence of various inhibitors to examine relevant signal pathways. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale.ResultsD-DT was inducibly expressed within astrocytes and neurons, rather than in microglia following spinal cord contusion. D-DT was able to activate the COX2/PGE2 signal pathway of astrocytes through CD74 receptor, and the intracellular activation of mitogen-activated protein kinases (MAPKs) was involved in the regulation of D-DT action. The selective inhibitor of D-DT was efficient in attenuating D-DT-induced astrocyte production of PGE2 following spinal cord injury, which contributed to the improvement of locomotor functions.ConclusionCollectively, these data reveal a novel inflammatory activator of astrocytes following spinal cord injury, which might be beneficial for the development of anti-inflammation drug in neuropathological CNS.

【 授权许可】

CC BY