Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis
Overview
Authors
Affiliations
In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.
Zadka L, Ustaszewski A, Glatzel-Plucinska N, Rusak A, Laczmanska I, Ratajczak-Wielgomas K Cancers (Basel). 2024; 16(21).
PMID: 39518103 PMC: 11545102. DOI: 10.3390/cancers16213665.
Saffron reduces the liver fibrosis in mice by inhibiting the JAK/STAT3 pathway.
Huang L, Han Y, Wang Z, Qiu Q, Yue S, Zhou Q Acta Cir Bras. 2023; 38:e385823.
PMID: 38055395 PMC: 10691186. DOI: 10.1590/acb385823.
Zhu Q, Korenfeld D, Suarez-Fueyo A, Graham S, Jin L, Punit S Mucosal Immunol. 2022; 15(6):1338-1349.
PMID: 36372810 DOI: 10.1038/s41385-022-00577-w.
Tyk2 is a tumor suppressor in colorectal cancer.
Moritsch S, Modl B, Scharf I, Janker L, Zwolanek D, Timelthaler G Oncoimmunology. 2022; 11(1):2127271.
PMID: 36185806 PMC: 9519006. DOI: 10.1080/2162402X.2022.2127271.
Medina-Larque A, Rodriguez-Daza M, Roquim M, Dudonne S, Pilon G, Levy E Front Immunol. 2022; 13:871080.
PMID: 36052065 PMC: 9424773. DOI: 10.3389/fimmu.2022.871080.