Interleukin-10 production by innate lymphoid cells restricts intestinal inflammation in mice

Mucosal Immunol. 2025 Jun;18(3):643-655. doi: 10.1016/j.mucimm.2025.02.005. Epub 2025 Feb 21.

Abstract

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 CX3CR1+ 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+ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR+ subtype. Interestingly, Ccl26 was enriched in IL-10+ ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX3CR1, 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 RorctdTomato reporter mice that faithfully marked RORγt+ 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.

Keywords: CCL26; CX(3)CR1; IBD; IL-10; ILC3.

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / metabolism
  • Colitis* / immunology
  • Colitis* / metabolism
  • Disease Models, Animal
  • Immunity, Innate*
  • Inflammation / immunology
  • Interleukin-10* / genetics
  • Interleukin-10* / metabolism
  • Intestinal Mucosa* / immunology
  • Intestinal Mucosa* / metabolism
  • Lymphocytes* / immunology
  • Lymphocytes* / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism

Substances

  • Interleukin-10
  • CX3C Chemokine Receptor 1
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rorc protein, mouse
  • Cx3cr1 protein, mouse
  • IL10 protein, mouse