mtROS-NF-κB signaling promotes ILC3 protective function and survival during sepsis-induced intestinal injury

Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity,yet their role in sepsis-associated colon injury remains unclear.Peripheral blood from healthy volunteers and septic patients was analyzed for ILC subset alterations.A LPS-induced murine sepsis model,combined with ILC3-deficient mice,was employed to assess ILC3 dynamic,function,metabolic features and impact on colon barrier interity using flow cytometry,histopathology,ELISA,RT-qPCR and in vitro co-culture experiments.Septic patients exhibited significantly reduced circulating ILC3 proportions.In mice,sepsis decreased colonic ILC3 numbers but enhanced IL-22 and GM-CSF production.ILC3 deficiency increased mortality and exacerbated intestinal barrier disruption,while exogenous IL-22/GM-CSF administration ameliorated colonic pathology.Mechanistically,sepsis induced metabolic reprogramming in ILC3,characteristiced by enhanced glycolysis,reduced mitochondrial mass and ATP producton,which led to mitochondrial ROS accumulation.ROS activated the NF-κB pathway to drive IL-22 and GM-CSF production.However,ROS scavening or NF-κB inhibition unexpectedly increased ILC3 apoptosis,revealing that ROS-NF-κB axis also conveys pro-survival signals.Despite enhanced function,the repair capacity of residual ILC3s was outpaced by ongoing intestinal destruction.Our finding provided insight into the relation of ROS-NF-κB axis with IL-22/GM-CSF production and the survival of remaining colonic ILC3s in sepsis.Thereby targeting this metabolic-immune crosstalk may present a therapeutic strategy to sepsis associated intestinal injury.