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.

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

“…Lastly and most importantly, treatment of CD8 ϩ T cells with ⌬ 9 -THC, a potent psychotropic anti-inflammatory cannabinoid in marijuana, effectively prevented CD8 ϩ T-cell activation and proliferation, miR-150 downregulation, and IRAK1 protein upregulation. Collectively, elevated IRAK1 protein expression in response to miR-150 downregulation may greatly facilitate the downstream transduction of proinflammatory signals, thus creating a persistent inflammatory environment in the intestine, as demonstrated recently using an IRAK1 knockout mouse model (51). In addition, our findings also suggest that cannabinoids provide a feasible strategy to decrease persistent immune activation/inflammation in HIV/ SIV infection.…”

“…Furthermore, mice lacking IRAK1 fail to mount an inflammatory response and produce significantly lower levels of proinflammatory cytokines, suggesting their critical requirement for activation of the NF-B signaling pathway and the subsequent inflammatory response (23). Finally, recent studies have confirmed the central role of IRAK1 in driving intestinal inflammation (50,51). Consistent with miR-150 downregulation, IRAK1 protein expression significantly increased in colonic LPLs of chronically SIV-infected macaques.…”

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Interleukin-17 Production via Activation of the IRAK1-PI3K-p38MAPK-C/EBPβ/CREB Pathways

“…Thus, it is possible that the interaction of nsp11 and IRAK1 triggers IRAK1 downstream activation to induce IL-17 production. It has been reported that IL-17 expression is reduced in IRAK-1 Ϫ/Ϫ mice, and these mice are protected from developing various inflammatory diseases (57,58).…”

A proteomics analysis reveals that A2M might be regulated by STAT3 in persistent allergic rhinitis

“…The positive correlation between A2M and IL‐17 in AR subjects might be due to the interactions among STAT3, A2M and IL‐17. STAT3 phosphorylation might activate A2M , thus enabling sustained IL‐17 production . Probably, IL‐17A might stimulate STAT3‐A2M axis through activating JAK2 and ERK1/2 .…”