Open AccessCD73 alleviates GSDMD‐mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling
Author(s) -
Xu Shun,
Wang Jin,
Zhong Junjie,
Shao Minghao,
Jiang Jianyuan,
Song Jian,
Zhu Wei,
Zhang Fan,
Xu Haocheng,
Xu Guangyu,
Zhang Yuxuan,
Ma Xiaosheng,
Lyu Feizhou
Publication year - 2021
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.269
Subject(s) - pyroptosis , microglia , neuroinflammation , pi3k/akt/mtor pathway , inflammasome , spinal cord injury , protein kinase b , medicine , microbiology and biotechnology , in vivo , cancer research , neuroscience , inflammation , spinal cord , immunology , signal transduction , biology
Abstract Background Neuroinflammation‐induced secondary injury is an important cause of sustained progression of spinal cord injury. Inflammatory programmed cell death pyroptosis executed by the pore‐forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation. However, it is unclear whether CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD. Methods C57BL/6J CD73 deficient mice and wild‐type mice, Lipopolysaccharide (LPS)‐induced primary microglia and BV2 cells were respectively used to illustrate the effect of CD73 on microglia pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and explore the mechanism both in vivo and in vitro. Results We have shown molecular evidence for CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in microglia. Further analysis reveals that adenosine‐A 2B adenosine receptor‐PI3K‐AKT‐Foxo1 cascade is a possible mechanism of CD73 regulation. Importantly, we determine that CD73 inhibits the expression of GSDMD at the transcriptional level through Foxo1. What's more, we confirm the accumulation of HIF‐1α promotes the overexpression of CD73 after spinal cord injury (SCI), and the increased CD73 in turn upregulates the expression of HIF‐1α, eventually forming a positive feedback regulatory loop. Conclusion Our data reveal a novel function of CD73 on microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI.