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

Huiyuan Ji,Bingqiang He,Xingyuan Zhang,Zhenjie Zhu,Chunshuai Sun,Chen Chen,Yongjun Wang,Yue Zhou,Huifei Hao,Aihong Li,Yuxin Zhang,Aisong Guo,Hui Li,Ting Yang,Yingjie Wang,Yuming Hu

doi:10.1186/s12974-021-02186-z

Abstract

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.

Highlights

Astrocytes 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
To elucidate the regulatory correlations between DDT and COX2 in the astrocytes, we synchronously examined the protein levels of COX1 and COX2, as well as the isoforms of Prostaglandin E2 (PGE2) synthase at the lesion sites following spinal cord injury (SCI) at 0 day, 1 day, 4 days, and 7 days
Results found that the protein levels of COX2 and microsomal PGE synthase-1, but not of COX1, mPGES2, and cytosolic PGE synthase, were inducibly expressed with a peak at 4 days following SCI (Fig. 3a– d)

Summary

Introduction

Astrocytes 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. Astrocytes are the predominant glial cell type in the central nervous system (CNS) performing a wide array of neurophysiological functions [1, 2]. It is clear they are essential for neuronal synaptogenesis, blood–brain barrier (BBB) formation, ion and water homeostasis, as well as recycle of neurotransmitter [3, 4]. Astrocytes are able to respond to and transmit danger signals via conversion of phenotype and secretion of cytokines and chemokines [5, 6]. Astrocytes are active players in the innate immunity of CNS, thereby has drawn much attention when dealing with CNS inflammation

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