The role of Interleukin-1 associated kinase 1 in intestinal inflammation

在炎症性肠病(IBD)中，肠道炎症被认为是由于上皮屏障功能缺陷导致对共生细菌的免疫反应失调，导致固有层底层的上皮细胞、树突状细胞(DC)和巨噬细胞过度刺激。活化的DC呈递管腔抗原，促进促炎效应T辅助细胞(Th)1和Th17细胞的扩增和分化，同时抑制调节性T细胞(Treg)的产生。由此导致的调节性和效应性Th细胞平衡的转变维持了慢性炎症反应。白介素1受体相关激酶(IRAK)在Toll样受体(TLRs)和IL-1受体下游的信号转导中起重要作用。磷酸化的IRAK1与肿瘤坏死因子受体相关因子6相互作用，导致核因子kB(NFkB)和丝裂原活化蛋白激酶的激活。IRAK1缺乏导致TLR和IL-1R触发的炎性细胞因子反应减少，但并未被消除，但IRAK1不是抗菌防御所必需的，使其成为安全的抑制靶点。最近的证据支持IRAK1在自身免疫和炎症性疾病中的重要作用。我们的假设是IRAK1参与了IBD肠道炎症的发病机制，可能是一个有吸引力的新的治疗靶点。在两个诱导性结肠炎模型中，我们在IRAK1缺陷小鼠身上获得的初步结果支持了这一假设，这些结果表明IRAK1在肠道炎症的发展中起着非多余的作用。目前还不清楚IRAK1信号在肠粘膜不同免疫和非免疫细胞类型中如何参与炎症反应。到目前为止，我们的结果表明T细胞中的IRAK1信号在结肠炎的发生中起主导作用，但也表明非T细胞中的IRAK1信号在结肠炎的发生中起着重要作用，包括天然免疫细胞和上皮细胞。因此，我们将研究：1)T细胞和非T细胞中的IRAK1信号对效应Th细胞和Treg的产生以及结肠炎时肠道聚集的特殊作用；2)肠上皮细胞中的IRAK1信号在结肠炎发展中的作用；3)IRAK1/4抑制剂在小鼠实验性结肠炎中的疗效；4)IRAK1在IBD患者肠粘膜中的表达以及IRAK1在人类Th细胞分化中的作用。

In inflammatory bowel diseases (IBD) intestinal inflammation is thought to be due to a dysregulated immune response to commensal bacteria due to a defective epithelial barrier function, which leads to overstimulation of epithelial cells, dendritic cells (DCs) and macrophages in the underlying lamina propria. Activated DCs present luminal antigens and promote the expansion and differentiation of proinflammatory effector T helper (Th)1 and Th17 cells while inhibiting regulatory T cell (Treg) generation. The resulting shift in the balance of regulatory to effector Th cells sustains the chronic inflammatory response. Interleukin-1 receptor associated kinases (IRAKs) are critically involved in signal transduction downstream of Toll-like receptors (TLRs) and the IL-1 receptor. Interaction of phosphorylated IRAK1 with tumor necrosis factor receptor associated factor 6 leads to the activation of nuclear factor k B (NFkB) and mitogen activated protein kinases. IRAK1 deficiency leads to a reduced but not abrogated inflammatory cytokine response to TLR and IL-1R triggering, but IRAK1 is not essential for antimicrobial defense making it a safe target for inhibition. Recent evidence support an important role of IRAK1 for autoimmune and inflammatory diseases.Our hypothesis is that IRAK1 is critically involved in the pathogenesis of intestinal inflammation in IBD and may be an attractive novel target for therapy. This hypothesis is supported by our preliminary results obtained with IRAK1-deficient mice in two inducible colitis models which demonstrate a non-redundant role of IRAK1 in the development of intestinal inflammation. It is not well understood how IRAK1 signaling in the different immune and non-immune cell types in the intestinal mucosa contributes to inflammation. Our results so far suggest that IRAK1 signaling in T cells plays a dominant role in colitis development, but also show a significant contribution of IRAK1 signaling in non-T cells, including innate immune cells and epithelial cells. In the proposed project we will therefore investigate: 1) the specific function of IRAK1 signaling in T cells and non-T cells for effector Th cell and Treg generation and intestinal accumulation during colitis, 2) the contribution of IRAK1 signaling in intestinal epithelial cells to colitis development, 3) the efficacy of an IRAK1/4 inhibitor in murine experimental colitis and 4) the expression of IRAK1 in intestinal mucosa of IBD patients as well as the role of IRAK1 for human Th cell differentiation.