Mesenchymal Stem Cells Improve the Prognosis of Sepsis Rats byAlleviating NLRP3-Caspase-1/Caspase-11-GSDMD-Mediated Pyroptosisof Peritoneal Macrophages

INTRODUCTION: Sepsis is a life-threatening condition and ranks among the leading causes of death worldwide. Bone marrow mesenchymal stem cells (BMSCs) have shown promise as a therapeutic strategy for sepsis due to their anti-inflammatory and immune-regulatory properties. However, the precise molecular mechanisms by which BMSCs exert these beneficial effects in sepsis are not yet fully elucidated. METHODS: We developed an in vitro macrophage injury model by co-culturing injured macrophages with BMSCs to evaluate pyroptosis. In vivo, we induced a sepsis model and subsequently transplanted BMSCs. The expressions of proteins involved in the NLRP3 (nod-like receptor family pyrin domain containing-3)-Caspase-1/Caspase-11-Gasdermin D (GSDMD) signaling pathway, as well as pyroptosis in peritoneal macrophages, were then investigated. RESULTS: Our results demonstrated that BMSCs co-cultured with lipopolysaccharide (LPS)-stimulated macrophages improved macrophage viability and reduced pyroptosis in vitro. Moreover, transplantation of BMSCs significantly decreased pyroptosis in peritoneal macrophages and improved the survival rate of sepsis rats. BMSC treatment also downregulated the expression levels of pyroptosis-related proteins in macrophages isolated from sepsis rats, including NLRP3, Caspase-1, Caspase-11, and GSDMD. DISCUSSION: These findings elucidate the mechanisms by which BMSCs exert therapeutic effects in sepsis, particularly through modulation of peritoneal macrophage pyroptosis. This provides a foundation for further research on sepsis and the potential clinical application of BMSCs. A limitation of this study is that the experimental results were derived from a rat model rather than non-human primates. CONCLUSION: This study demonstrates that transplantation of BMSCs may suppress NLRP3-Caspase- 1/Caspase-11-GSDMD-mediated pyroptosis in peritoneal macrophages during sepsis, providing new mechanistic insights into the therapeutic effects of BMSCs.