title: IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity.
abstract: 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.
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany;
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Heiseke
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany;
authors.forename: Benjamin H
authors.identifier: http://orcid.org/0000-0002-9071-7464
authors.initials: BH
authors.lastname: Jeuk
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany;
authors.forename: Anamarija
authors.initials: A
authors.lastname: Markota
authors.affiliation: Bioinformatics Core Unit, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Straub
authors.affiliation: Institut für Pathologie, Medizin Campus Bodensee, Friedrichshafen, D-88048 Friedrichshafen, Germany; and.
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.affiliation: Klinikum Mannheim II, Medizinische Klinik, D-68167 Mannheim, Germany.
authors.forename: Wolfgang
authors.identifier: http://orcid.org/0000-0002-6982-8506
authors.initials: W
authors.lastname: Reindl
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany; anne.krug@med.uni-muenchen.de.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Krug
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D003092:Colitis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology*; D016023:Integrins / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology; D007422:Intestines / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D016201:Receptors, Lymphocyte Homing / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology* / Q000637:transplantation
chemical_list: D016207:Cytokines; D016023:Integrins; D020381:Interleukin-17; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7; D053592:Interleukin-1 Receptor-Associated Kinases