CD73 alleviates GSDMD‐mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling. Issue 1 (31st December 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Clinical and translational medicine. Volume 11:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-31
• Subjects: Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.269
• Languages: English
• ISSNs: 2001-1326

Abstract

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‐A2B 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. Abstract : Inflammatory programmed cell death pyroptosis executed by the pore‐forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation after spinal cord injury. We demonstrated that CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD through PI3K/AKT/Foxo1 signaling.