Valle-Noguera, AnaSancho-Temiño, LucíaCastillo-González, RaquelVilla-Gómez, CristinaGomez-Sánchez, María JoséOchoa-Ramos, AnneYagüe-Fernández, PatriciaSoler Palacios, BlancaZorita, VirginiaRaposo-Ponce, BertaGonzález-Granado, José MaríaAragonés, JuliánCruz-Adalia, Aránzazu2024-05-072024-05-072023-12-26Cell Rep. 2023 Dec 26;42(12):113508.http://hdl.handle.net/20.500.12105/19273Group 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-1α in ILC3s and other innate RORγt+ cells during in vivo infections are poorly understood. In our study, transgenic mice with specific Hif-1a gene inactivation in innate RORγt+ cells (RAG1KO HIF-1α▵Rorc) exhibit more severe colitis following Citrobacter rodentium infection, primarily due to the inability to upregulate IL-22. We find that HIF-1α▵Rorc mice have impaired IL-22 production in ILC3s, while non-ILC3 innate RORγt+ 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-1α, 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-1α in ILC3s, which is crucial for protection against this pathogen.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/InterleukinsColitisMiceAnimalsImmunity, InnateNuclear Receptor Subfamily 1, Group F, Member 3LymphocytesInterleukin-18InflammationMice, TransgenicMice, Inbred C57BLAttribution-NonCommercial-NoDerivatives 4.0 Internacional38019650421211350810.1016/j.celrep.2023.1135082211-1247Cell reportsopen access