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

• Published in: Cell reports (Cambridge) Vol. 42; no. 12; p. 113508
• Main Authors: Valle-Noguera, Ana, Sancho-Temiño, Lucía, Castillo-González, Raquel, Villa-Gómez, Cristina, Gomez-Sánchez, María José, Ochoa-Ramos, Anne, Yagüe-Fernández, Patricia, Soler Palacios, Blanca, Zorita, Virginia, Raposo-Ponce, Berta, González-Granado, José María, Aragonés, Julián, Cruz-Adalia, Aránzazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.12.2023; Elsevier
• Subjects: Animals; Citrobacter rodentium; Colitis; CP: Immunology; group 3 innate lymphoid cells; HIF-1α; IL-18; IL-22; Immunity, Innate; infection; Inflammation; innate RORγt+ cells; Interleukin-18; Interleukins - genetics; Interleukins - metabolism; Lymphocytes - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; TLR2; CP: Immunology; infection; colitis; IL-18; innate RORγt+ cells; HIF-1α; Citrobacter rodentium; group 3 innate lymphoid cells; IL-22; TLR2; innate RORγt(+) cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113508

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-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. [Display omitted] •C. rodentium induces production of IL-18 in colon, which upregulates HIF-1α in ILC3s•IL-18 production in the colon is boosted by TLR2 signaling•HIF-1α promotes IL-22 in ILC3s and not in other innate RORγt+ cells after infection•IL-18 is responsible for the production of IL-22 by colonic ILC3s through HIF-1α HIF-1α is a hypoxia-inducible factor regulating several immune cells in the response against infections. Valle-Noguera et al. evaluates the function of HIF-1α in colonic ILC3s during C. rodentium infection in mice, demonstrating that TLR2-induced IL-18 transcriptionally upregulates HIF-1α in ILC3s, boosting IL-22 secretion to protect against the infection.