IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity
IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity
复制标题
DOI：
10.4049/jimmunol.1501874
复制
发表时间：
2015-12-15
影响因子：
4.4
通讯作者：
Krug, Anne B.
中科院分区：
文献类型：
--
作者：
Heiseke, Alexander F.;Jeuk, Benjamin H.;Krug, Anne B.
IL-1R 相关激酶 (IRAK) 1 是 IL-1R 和 TLR 信号通路的重要组成部分，影响 Th 细胞分化。在这项研究中，我们发现IRAK1通过介导IL-1β诱导的IL-23R上调和随后的STAT3磷酸化来促进Th17发育，从而实现IL-17的持续产生。此外，我们还发现，IRAK1 信号传导通过介导 T-bet 诱导来促进 Th1 分化，并抵消调节性 T 细胞的生成。共转移实验表明，Irak1缺陷型CD4+T细胞在脾脏、肠系膜淋巴结和结肠组织的炎症条件下产生Th1和Th17细胞方面存在细胞内在缺陷。此外，T 细胞中的 IRAK1 表达对于发炎肠道和肠系膜淋巴结中 T 细胞的积累至关重要。离体转录组分析表明，IRAK1 以细胞固有的方式促进 T 细胞激活和诱导肠道归巢分子。因此，Irak1缺陷的T细胞在转移到Rag1(-/-)小鼠体内后未能上调α4β7整合素的表面表达，并且其诱导结肠炎的能力大大受损。受体小鼠缺乏 IRAK1 可以提供额外的结肠炎保护。因此，IRAK1通过介导肠道内T细胞的激活、分化和积累在肠道炎症中发挥重要作用。因此，IRAK1是治疗炎症性肠病的一个有前途的新靶点。
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-1 beta-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 alpha 4 beta 7 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.