IL-18-induced HIF-1a in ILC3s ameliorates the inflammation of C. rodentium-induced colitis

Group 3 innate lymphoid cells (ILC3s) are vital for defending tissue barriers from invading pathogens. Hypoxia influences the production of intestinal ILC3-derived cytokines by activating HIF. Yet, the mechanisms governing HIF-1 alpha in ILC3s and other innate RORgt+ cells during in vivo infections are poorly understood. In our study, transgenic mice with specific Hif-1a gene inactivation in innate RORgt(+) cells (RAG1KO HIF1 alpha(Delta Rorc)) exhibit more severe colitis following Citrobacter rodentium infection, primarily due to the inability to upregulate IL -22. We find that HIF-1 alpha(Delta Rorc)mice have impaired IL -22 production in ILC3s, while nonILC3 innate RORgt+ cells, also capable of producing IL -22, remain unaffected. Furthermore, we show that IL -18, induced by Toll -like receptor 2, selectively triggers IL -22 in ILC3s by transcriptionally upregulating HIF-1 alpha, revealing an oxygen -independent regulatory pathway. Our results highlight that, during late -stage C. rodentium infection, IL -18 induction in the colon promotes IL -22 through HIF-1 alpha in ILC3s, which is crucial for protection against this pathogen.