IL-33 Drives Expansion of Type 2 Innate Lymphoid Cells and Regulatory T Cells and Protects Mice From Severe, Acute Colitis

• Published in: Frontiers in immunology 2021-07, Vol.12, p.669787
• Main Authors: Ngo Thi Phuong, Nhi, Palmieri, Vittoria, Adamczyk, Alexandra, Klopfleisch, Robert, Langhorst, Jost, Hansen, Wiebke, Westendorf, Astrid M, Pastille, Eva
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Anti-Inflammatory Agents - pharmacology; Cell Proliferation - drug effects; colitis; Colitis - chemically induced; Colitis - immunology; Colitis - metabolism; Colitis - prevention & control; Colon - drug effects; Colon - immunology; Colon - metabolism; Colon - pathology; Dextran Sulfate; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Goblet Cells - immunology; Goblet Cells - metabolism; Humans; IL-33; ILC2; Immunity, Innate - drug effects; Immunology; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33 - pharmacology; intestinal inflammation; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; ST2; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tregs
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.669787

The hallmarks of inflammatory bowel disease are mucosal damage and ulceration, which are known to be high-risk conditions for the development of colorectal cancer. Recently, interleukin (IL)-33 and its receptor ST2 have emerged as critical modulators in inflammatory disorders. Even though several studies highlight the IL-33/ST2 pathway as a key factor in colitis, a detailed mode of action remains elusive. Therefore, we investigated the role of IL-33 during intestinal inflammation and its potential as a novel therapeutic target in colitis. Interestingly, the expression of IL-33, but not its receptor ST2, was significantly increased in biopsies from the inflamed colon of IBD patients compared to non-inflamed colonic tissue. Accordingly, in a mouse model of Dextran Sulfate Sodium (DSS) induced colitis, the secretion of IL-33 significantly accelerated in the colon. Induction of DSS colitis in mice displayed an aggravated colon pathology, which suggested a favorable role of the IL 33/ST2 pathway during colitis. Indeed, injecting rmIL-33 into mice suffering from acute DSS colitis, strongly abrogated epithelial damage, pro-inflammatory cytokine secretion, and loss of barrier integrity, while it induced a strong increase of Th2 associated cytokines (IL-13/IL-5) in the colon. This effect was accompanied by the accumulation of regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) in the colon. Depletion of Foxp3 Tregs during IL-33 treatment in DSS colitis ameliorated the positive effect on the intestinal pathology. Finally, IL-33 expanded ILC2s, which were adoptively transferred to DSS treated mice, significantly reduced colonic inflammation compared to DSS control mice. In summary, our results emphasize that the IL-33/ST2 pathway plays a crucial protective role in colitis by modulating ILC2 and Treg numbers.