Eliminating myeloid-derived suppressor cells alleviates immunosuppression and reduces susceptibility to secondary infections in a two-hit sepsis model.

Myeloid-derived suppressor cells (MDSCs) are known for their immunosuppressive effects on both innate and adaptive immunity, particularly targeting T cells, and they undergo continuous expansion during sepsis. However, the pathophysiological significance of MDSCs in sepsis-induced immunosuppression remains to be fully elucidated. In this study, we investigated the dynamic changes in MDSCs during sepsis and their contribution to sepsis-induced immunosuppression using a clinically relevant "two-hit" sepsis model. Our findings revealed that mice surviving cecal ligation and puncture (CLP) exhibited a significant accumulation and enhanced activity of MDSCs, which correlated with sepsis-related immune paralysis, impaired bacterial clearance, and heightened susceptibility to secondary infections. Importantly, administration of the liver X receptor (LXR) agonist GW3965 at the late stage of sepsis significantly restored immune function, decreased susceptibility to secondary infections, enhanced bacterial clearance, and improved prognosis by eliminating MDSCs. These results highlight the pivotal role of MDSCs in the development of sepsis-associated immunosuppression and indicate that targeting MDSCs could be a promising therapeutic approach to mitigate immunosuppression in sepsis.