Microbial Regulation of Retinol Transport and its Role in Intestinal Immunity

项目摘要 肠上皮细胞调节对肠道微生物的适应性免疫的发展，但很少有 了解潜在的机制。填补这一知识空白至关重要，因为许多人类肠道 肠道免疫失调引起的疾病。饮食中的维生素A被肠上皮吸收， 对于针对微生物群的关键适应性免疫反应至关重要。这些包括CD4+ T细胞的归巢， 肠和产生免疫球蛋白A的B细胞的发育。这些反应取决于 特化的肠树突状细胞（DC），其将维生素A衍生物视黄醇酶促转化为视黄酸 酸（RA）。一个主要的未回答的问题是RA生产DC如何获得他们的视黄醇。视黄醇类脂质 化学性质使其必须通过保护视黄醇免受水环境影响的蛋白质进行转运。 然而，将视黄醇从肠上皮细胞动员到作为RA底物的DCs的蛋白质， 生产仍然未知。通过对血清淀粉样蛋白A（SAA）的研究，我们对这一问题有了深入的认识 蛋白质，其由肠上皮响应于微生物群而产生。此次R01更新 应用将探讨血清淀粉样蛋白A（SAA）蛋白动员视黄醇产生RA的假设， DC，从而形成肠道适应性免疫。在上一个项目期间，我们发现SaaS 在急性全身感染期间与结合的视黄醇一起循环的视黄醇结合蛋白。进一步的初步 研究结果表明，肠道SAA促进产生RA的DC获得视黄醇。我们建议， 这些发现在下一个项目期间，以获得更深层次的机械理解， 肠道DC功能和肠道适应性免疫的发展。在目标1中，我们将描述 SAA在肠道树突状细胞的视黄醇获取和视黄酸产生中的作用。在目标2中，我们将确定 视黄醇结合的SAA的细胞受体。在目标3中，我们将确定SAA的生理相关性 维生素A依赖的适应性免疫在肠道的发展。这些研究将提供 深入了解维生素A是如何被动员到肠道免疫细胞的，并推进我们的理解 微生物与上皮细胞的相互作用如何塑造适应性免疫。了解微生物群如何控制 维生素A依赖性免疫将促进炎症性疾病的新疗法的设计， 预防感染的疫苗。

Project Summary The intestinal epithelium regulates the development of adaptive immunity to gut microorganisms, yet little is known about the underlying mechanisms. Filling this knowledge gap is crucial, as many human intestinal diseases arise from dysregulated intestinal immunity. Dietary vitamin A absorbed by the intestinal epithelium is essential for key adaptive immune responses to the microbiota. These include the homing of CD4+ T cells to the intestine and the development of B cells that produce immunoglobulin A. These responses depend on specialized intestinal dendritic cells (DCs) that enzymatically convert the vitamin A derivative retinol to retinoic acid (RA). A major unanswered question is how RA-producing DCs acquire their retinol. Retinol's lipid-like chemical nature necessitates its transport by proteins that protect the retinol from the aqueous environment. However, the protein(s) that mobilize retinol from the intestinal epithelium to DCs as substrate for RA production remain unknown. We have gained insight into this question by studying serum amyloid A (SAA) proteins, which are produced by the intestinal epithelium in response to the microbiota. This R01 renewal application will explore the hypothesis that serum amyloid A (SAA) proteins mobilize retinol to RA-producing DCs and thus shape intestinal adaptive immunity. In the previous project period, we discovered that SAAs are retinol-binding proteins that circulate with bound retinol during acute systemic infection. Further preliminary findings indicate that intestinal SAAs promote retinol acquisition by RA-producing DCs. We propose to build on these findings during the next project period to gain a deeper mechanistic understanding of how SAAs shape intestinal DC function and the development of intestinal adaptive immunity. In Aim 1, we will delineate the role of SAAs in retinol acquisition and retinoic acid production by intestinal dendritic cells. In Aim 2, we will identify the cellular receptor for retinol-bound SAAs. In Aim 3, we will determine the physiological relevance of SAAs for the development of vitamin A-dependent adaptive immunity in the intestine. These studies will provide mechanistic insight into how vitamin A is mobilized to intestinal immune cells and advance our understanding of how microbiota-epithelial interactions shape adaptive immunity. Understanding how the microbiota controls vitamin A-dependent immunity will promote the design of new therapeutics for inflammatory disorders and vaccines against infections.