mtROS-NF-κB signaling supports ILC3 function and survival during sepsis-induced intestinal injury.

Sepsis frequently induces intestinal barrier injury, which exacerbates systemic inflammation, and contributes to high mortality. Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity, yet their role in sepsis-associated intestinal injury remains incompletely understood. We found circulating ILCPs were reduced in patients with sepsis. In an LPS-induced murine sepsis model, colonic ILC3 numbers declined whereas the residual population showed increased frequencies of IL-22- and GM-CSF-producing cells. RORγt-deficient mice exhibited impaired induction of colonic IL-22 and GM-CSF, increased intestinal permeability, and aggravated histopathological injury. Adoptive transfer of purified wild-type ILC3s restored colonic IL-22 and GM-CSF levels and partially improved barrier integrity. Mechanistically, septic ILC3s showed hypoxia-associated mitochondrial impairment and accumulation of mitochondrial ROS. increased mtROS contributed to enhanced NF-κB p65 phosphorylation and selectively supported IL-22 and GM-CSF production. Recombinant IL-22 or GM-CSF ameliorated intestinal injury. However, ROS scavenging or NF-κB inhibition increased ILC3 apoptosis, indicating that ROS-NF-κB axis also supports residual ILC3 survival. Together, these findings identify a mitochondria-associated ROS-NF-κB program that sustains protective cytokine production and survival in residual intestinal ILC3s during sepsis, although it is insufficient to prevent ongoing ILC3 loss and intestinal injury.