Intestinal IL-17RA signaling and mucosal host defense

炎症性肠病(IBD)包括溃疡性结肠炎(UC)和克罗恩病(CD)，是一种 影响美国数百万人的毁灭性疾病。主导的潜在机制 人们对IBD知之甚少。Paneth细胞及其抗菌产物(a-防御素、溶菌酶等)播放 在小肠宿主防御中的关键作用及其失调构成了CD的致病因素。光盘 患者存在潘氏细胞异常，α-防御素表达减少，IL-17A水平升高 发炎的组织。IL-17A/IL-17F轴是肠道炎症和保护性的已知驱动因素 在小鼠模型和人类IBD模型中的反应，但对IL-2的特定细胞生态位知之甚少。 肠道17A/F受体信号转导及IL-17A介导宿主防御的分子机制我们 我们首次表明，消除肠道IL-17A宿主防御反应会导致共生 小肠中的生物失调和免疫反应失调。尽管有无数的胃肠道疾病 对于IL-17A刺激的肠道反应，文献未能阐明是否对 损伤或感染是直接刺激功能不同的吸收或分泌成熟的结果。 无论是上皮细胞类型还是干细胞衍生的结果。因此，目前尚不清楚IL-17A 直接或间接地调节肠道中的Paneth和其他细胞类型的效应器功能。我们发现IL-17A/F 受体(IL-17RA/IL-17RC)表达于功能不同的吸收细胞(肠细胞)、分泌细胞 (Paneth)、Lgr5+肠道干细胞(ISCs)和肠道转运扩增(TA)祖细胞。 然而，关于IL-17A是否直接或间接调节Paneth细胞，ISCs，几乎一无所知 和祖细胞的功能。我们现在有令人信服的证据表明IL-17A直接调节 在肠道的Paneth细胞、ISCs和Atoh1+祖细胞中具有独特和特定的功能。Atoh1是 肠道分泌细胞，包括潘氏细胞的谱系承诺所必需的。为了调查血统- 特定的功能，我们建立并验证了完整的肠道上皮(Villin-cre)、Paneth细胞(Defa6-cre)和 Atoh1特异性(Atoh1-cre)新型IL-17RA(Il17rafl/fl)条件性基因敲除小鼠。目标1中的拟议研究 将试图了解IL-17RA信号在调节ISC和Paneth细胞功能中的作用 动态平衡状态。在目标2中，使用多种肠道炎症模型和我们的谱系特异性IL-2 17RA条件性基因敲除小鼠，我们将确定IL-17A如何在特定的 小肠和大肠的细胞类型。这些研究将对IBD研究产生直接影响 了解IL-17RA信号转导小肠和大肠主要细胞类型的新作用。完成 这些研究将提供对IL-2作用的复杂分子机制的必要了解。 17A在调节肠道炎症中的作用。

Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a devastating disease that impacts millions of people in the United States. The underlying mechanisms leading to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL- 17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells (Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine. However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage- specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1 will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL- 17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion of these studies will provide a needed understanding of the complex molecular mechanisms of actions of IL- 17A in regulating intestinal inflammation.