Interleukin-10 production by innate lymphoid cells restricts intestinal inflammation in mice
Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX<sub>3</sub>CR1<sup>+</sup> mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10<sup>+</sup> producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR<sup>+</sup> subtype. Interestingly, Ccl26 was enriched in IL-10<sup>+</sup> ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX<sub>3</sub>CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated transgenic Rorc<sup>tdTomato</sup> reporter mice that faithfully marked RORγt<sup>+</sup> cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages.
Authors
- Mark Rusznak
- Yash A. Choksi (ORCID: https://orcid.org/0000-0003-1717-4472)
- Justin Jacobse (ORCID: https://orcid.org/0000-0002-1899-0319)
- Weihong Gu (ORCID: https://orcid.org/0000-0002-0111-9949)
- Jennifer M. Pilat (ORCID: https://orcid.org/0000-0001-5385-3232)
- Jeremy A. Goettel (ORCID: https://orcid.org/0000-0002-0749-2357)
- Keith T. Wilson (ORCID: https://orcid.org/0000-0003-4421-1830)
- Harsimran Kaur (ORCID: https://orcid.org/0000-0003-2667-1091)
- Caroline V. Hawkins
- Hsin-I Huang (ORCID: https://orcid.org/0000-0001-9106-9449)
- Liza Konnikova (ORCID: https://orcid.org/0000-0003-4804-5497)
- Ken S. Lau (ORCID: https://orcid.org/0000-0001-8438-0319)
- Gianna Hammer (ORCID: https://orcid.org/0000-0001-6959-858X)
- Seungwoo Kang (ORCID: https://orcid.org/0000-0003-1301-8480)
- Christopher S. Williams (ORCID: https://orcid.org/0000-0002-1541-579X)
- R. Stokes Peebles (ORCID: https://orcid.org/0000-0002-1429-7875)
- M. Kay Washington (ORCID: https://orcid.org/0000-0002-9589-7695)
- Jing Li
- Andrew P Pahnke (ORCID: https://orcid.org/0009-0000-2761-369X)
- Joseph T. Roland
- Julio Barrera
- M. Khalil
- Pauline A Oloo
Institutions
- Vanderbilt University (US)
- University of Utah (US)
- Leiden University Medical Center (NL)
- Yale University (US)
- VA Tennessee Valley Healthcare System (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Mucosal Immunology
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1016/j.mucimm.2025.02.005
- Citations
- 4
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- U.S. Department of Veterans Affairs
- Burroughs Wellcome Fund
- Crohn's and Colitis Foundation of America
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Vanderbilt-Ingram Cancer Center
- Koninklijke Nederlandse Akademie van Wetenschappen
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases