Paneth cell-specific IL-22Ra1 signaling in mucosal host defense

粘膜宿主防御中潘氏细胞特异性 IL-22Ra1 信号传导

• 批准号: 10092946
• 负责人: Pawan Kumar
• 金额: $ 23.6万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092946
• 关键词: Address; Cell Compartmentation; Cell Lineage; Cells; Chimeric Proteins; Collaborations; Colon; Colorectal Cancer; Coupled; Data; Defect; Defensins; Development; Disease; EGF gene; Effector Cell; Enterocytes; Environment; Epithelial; Epithelial Cells; Goals; Growth Factor; Host Defense; Human; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestines; Knockout Mice; Knowledge; LGR5 gene; Lymphoid Cell; Maintenance; Mediating; Modeling; Molecular; Mucous Membrane; Mus; Nature; Paneth Cells; Pathogenesis; Pathway interactions; Play; Post-Translational Protein Processing; Predisposition; Proteins; Receptor Signaling; Recombinant Interleukins; Research Design; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Signal Transduction; Small Intestines; Tamoxifen; Testing; Therapeutic; Universities; antimicrobial peptide; base; cell regeneration; cell type; commensal bacteria; conditional knockout; defense response; design; dextran sulfate sodium induced colitis; experience; gastrointestinal epithelium; inflammatory disease of the intestine; insect defensin A; interleukin-22; interleukin-23; intestinal epithelium; microbiota; mouse model; novel; pleiotropism; receptor; response; stem cell niche; stem cells; synergism; therapy outcome; tool; villin

Interleukin (IL)-22, which is derived from innate lymphoid cells (ILC)-3 and Th17 cells, plays an important role in intestinal host defense since mice deficient in IL-22 or its receptor, IL-22Ra1, are highly susceptible to multiple models of intestinal inflammation. In the past 10 years substantial progress has been made in our understanding of the IL-22-mediated mucosal host defense responses in the intestine; however, serious gaps in our knowledge remain. The pleiotropic effects of IL-22, coupled with the diverse array of intestinal cell types that express IL- 22Ra1, limit our ability to target this pathway therapeutically. It remains unclear how IL-22 interacts with functionally distinct epithelial cell lineages (absorptive or secretory) and intestinal stem cells (ISCs). The goal of this proposal is to understand whether IL-22Ra1 signaling in Paneth and/or intestinal stem cell (ISCs) regulates IL-22-mediated protection. We will assess the mechanistic nature of that protection on distinct epithelial compartments using cell-specific knockout mice and recombinant IL-22.Fc protein approaches. Towards this end, we generated 1) entire gut epithelium, 2) Lgr5+ ISCs, and 3) Paneth cell-specific conditional IL-22Ra1 knockout mice. We have accumulated critical data that lack of intestinal IL-22Ra1 signaling leads to a defect in Paneth cell-specific functions as well as enhanced susceptibility to Salmonella Typhimurium. Thus, based on the strength of our preliminary results, we hypothesize that IL-22Ra1 signaling in Paneth cells modulates intestinal host defense by regulating post-translational modifications of a-defensins and maintaining ISCs niche. In specific Aim 1, we will determine whether IL-22Ra1 signaling in Paneth cells regulates post-translational modification of a-defensins and maintains ISCs niche. In Aim 2, we will investigate whether Paneth, ISCs and/or absorptive enterocytes-specific role of IL-22Ra1 signaling is required to control S. Typhimurium-induced inflammation. These studies will provide critical new mechanistic information about specific cellular niches of IL- 22Ra1-signaling in the gut and their involvement in disease development, maintenance and therapeutic outcomes.

白细胞介素（IL）-22来源于先天性淋巴样细胞（ILC）-3和Th 17细胞，在免疫调节中起重要作用。 肠道宿主防御，因为IL-22或其受体IL-22 Ra 1缺陷小鼠对多种 肠道炎症模型。在过去10年中，我们在理解 IL-22介导的肠道粘膜宿主防御反应;然而，我们的知识存在严重差距， 保持。IL-22的多效性作用，加上表达IL-22的多种肠细胞类型， 22 Ra 1，限制了我们在治疗上靶向这一途径的能力。目前尚不清楚IL-22如何与 功能不同的上皮细胞谱系（吸收或分泌）和肠干细胞（ISCs）。的目标 该建议是为了了解潘氏和/或肠干细胞（ISCs）中的IL-22 Ra 1信号传导是否调节 IL-22介导的保护。我们将评估这种保护作用对不同上皮细胞的机制性质， 使用细胞特异性敲除小鼠和重组IL-22.Fc蛋白方法，在细胞区室中进行细胞内表达。为实现这一 最后，我们产生了1）完整的肠上皮，2）Lgr 5 + ISCs，和3）潘氏细胞特异性条件性IL-22 Ra 1 敲除小鼠我们已经积累了关键数据，即肠道IL-22 Ra 1信号传导的缺乏导致肠道免疫缺陷。 Paneth细胞特异性功能以及对鼠伤寒沙门氏菌的易感性增强。因此，基于 根据我们初步结果的强度，我们假设潘氏细胞中的IL-22 Ra 1信号转导调节 通过调节α-防御素的翻译后修饰和维持ISCs生态位来调节肠道宿主防御。 在特定的目标1中，我们将确定潘氏细胞中的IL-22 Ra 1信号传导是否调节翻译后 修饰α-防御素并维持ISCs生态位。在目标2中，我们将调查Paneth、ISC和/或 需要IL-22 Ra 1信号传导的吸收性肠细胞特异性作用来控制S. Typhimurium诱导 炎症这些研究将提供关于IL-10的特定细胞小生境的关键新机制信息。 肠道中的22 Ra 1信号传导及其在疾病发展、维持和治疗中的作用 结果。