CD73 alleviates GSDMD-mediated pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

Abstract

Background: Neuroinflammation-induced secondary injury is responsible for the sustained progression of spinal cord injury (SCI). Inflammatory programmed cell death or pyroptosis triggered by the pore-forming protein gasdermin D (GSDMD) is an essential step in neuroinflammation. The aim of this study was to determine the role of the immunosuppressive receptor CD73 in GSDMD-mediated pyroptosis following SCI. Methods: CD73 deficient mice and LPS-stimulated BV2 cells were respectively used as the in vivo and in vitro models of microglial pyroptosis. Molecular and histological assays were performed to assess pyroptosis and inflammasome activation, and to explore the underlying mechanisms.Results: CD73 inhibited the NLRP3 inflammasome and GSDMD, and decreased pyroptosis in the microglia via the adenosine-A2B adenosine receptor (AR)-PI3K-AKT-FOXO1 pathway. Specifically, CD73 suppressed GSDMD at the transcriptional level through FOXO1. Furthermore, HIF-1α accumulation after SCI upregulated CD73, which in turn increased the expression of HIF-1α, resulting in a positive feedback regulatory loop.Conclusion: CD73 alleviates microglial pyroptosis after SCI by inhibiting GSDMD via the adenosine- A2BAR-PI3K-AKT-FOXO1 pathway.

Exosomal miR-27b-3p Derived from Hypoxic Cardiac Microvascular Endothelial Cells Alleviates Rat Myocardial Ischemia/Reperfusion Injury through Inhibiting Oxidative Stress-Induced Pyroptosis via Foxo1/GSDMD Signaling

“…Foxo1 acts as a transcription factor and has multiple functions through interacting with targets, including angiogenesis-related molecules [49]. Foxo1 could be influenced by various environmental stimuli including CK, oxidative stress, and hypoxia as well as various signaling such as Akt, NF-κB, STAT3, and ERK1/2 [50][51][52] and is cor-related with cellular behaviors including cell proliferation, differentiation, autophagy, cell cycle distribution, apoptosis, and DNA repair [53]. NLRP3 inflammasome-mediated pyroptosis was associated with Foxo1 [54,55].…”