Shun Xu1,2, Jin Wang2, Junjie Zhong3,4,5,6, Minghao Shao2, Jianyuan Jiang2, Jian Song2, Wei Zhu2, Fan Zhang2, Haocheng Xu2, Guangyu Xu2, Yuxuan Zhang2, Xiaosheng Ma2, Feizhou Lyu1,2. 1. Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. 2. Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China. 3. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. 4. Neurosurgical Institute of Fudan University, Fudan University, Shanghai, China. 5. Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China. 6. Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China.
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.
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.
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