CD73 Alleviates GSDMD-Mediated Pyroptosis in Spinal Cord Injury Through PI3K/AKT/Foxo1 Signaling

Abstract

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 recently regarded as an essential step of neuroinflammation. However, it is unclear whether CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD. Here, we reported molecular evidence for CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in macrophages/microglia. Further analysis revealed that adenosine-A2B adenosine receptor-NF-κB cascade is a possible mechanism of CD73 regulation. Importantly, we determined that CD73 inhibited the expression of GSDMD at the transcriptional level through NF-κB, thereby alleviating macrophages/microglia pyroptosis. What’s more, we confirmed the accumulation of HIF-1α promotes the overexpression of CD73 after SCI, and the increased CD73 in turn upregulates the expression of HIF-1α, eventually forming a positive feedback regulatory loop. In summary, our results demonstrate that CD73 alleviates GSDMD-mediated pyroptosis of macrophages/microglia in spinal cord injury by blocking NF-κB signal. Our data reveal a novel function of CD73 on microphages/microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI. Funding Statement: This work was supported by the National Natural Science Foundation of China [grant number 81772385, 81871522]. Declaration of Interests: The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Ethics Approval Statement: All study surgical procedures and experiment protocols were performed in accordance with standard guidelines approved by the Ethics Committee of Experimental Research, Shanghai Medical College, Fudan University (Shanghai, China). The animal experiments were approved by the Institutional Animal Care and Use Committee of Fudan University.