IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

IL-1R-associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1β-induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabli...

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Published in:	The Journal of immunology (1950) Vol. 195; no. 12; pp. 5787 - 5794
Main Authors:	Heiseke, Alexander F, Jeuk, Benjamin H, Markota, Anamarija, Straub, Tobias, Lehr, Hans-Anton, Reindl, Wolfgang, Krug, Anne B
Format:	Journal Article
Language:	English
Published:	United States 15-12-2015
Subjects:	Adoptive Transfer Animals Cell Differentiation Cell Movement - genetics Colitis - immunology Cytokines - immunology Cytokines - metabolism Inflammation - immunology Inflammatory Bowel Diseases - drug therapy Inflammatory Bowel Diseases - immunology Integrins - metabolism Interleukin-1 Receptor-Associated Kinases - genetics Interleukin-1 Receptor-Associated Kinases - metabolism Interleukin-17 - immunology Intestines - immunology Lymphocyte Activation Mice Mice, Inbred C57BL - genetics Mice, Inbred C57BL - metabolism Mice, Knockout Receptors, Lymphocyte Homing - genetics Receptors, Lymphocyte Homing - metabolism Signal Transduction - immunology T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - transplantation Th17 Cells - immunology Th17 Cells - transplantation
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Summary:	IL-1R-associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1β-induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4(+) T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1(-/-) mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1501874