Microbial Regulation of Retinol Transport and its Role in Intestinal Immunity

项目摘要 肠道上皮调节对肠道微生物的适应性免疫的发展，但几乎没有。 了解其潜在的机制。填补这一知识缺口至关重要，因为许多人类肠道 疾病是由肠道免疫功能失调引起的。肠道上皮吸收的膳食维生素A是 对关键的肠道适应性免疫反应是必不可少的，包括T和B细胞归巢到肠道 和免疫球蛋白A的产生。这些依赖维生素A的免疫反应依赖于特定的 肠道髓系细胞，可将维生素A衍生物视黄醇酶促转化为维甲酸(RA)。在 在之前的项目期间，我们揭开了肠道髓系细胞获得视黄醇的分子机制。 我们发现血清淀粉样蛋白A(SAA)--微生物区系诱导的上皮细胞蛋白--是视黄醇 通过内吞受体LRP1(低密度脂蛋白相关)向髓系细胞递送视黄醇的伴侣 受体1)。我们发现这一机制对肠道获得性免疫的发展是必不可少的。 对致病细菌感染具有免疫保护作用。此R01续订申请将建立在以下基础之上 进一步确定调节视黄醇的生化、细胞生物学和微生物机制的研究结果 运送到肠道髓系细胞，从而促进维生素A依赖的免疫。在目标1中，我们将确定 肠上皮细胞如何组装和分泌SAA-视黄醇复合体。在目标2中，我们将确定 SAA-LRP1的相互作用及其对髓细胞视黄醇摄取和维生素A依赖的重要性 豁免权。在目标3中，我们将确定肠道微生物区系在调节髓系细胞视黄醇获取中的作用。 和维生素A依赖的免疫力。这些研究将提供对维生素A是如何动员起来的机械性洞察 肠道免疫细胞，促进我们对肠道微生物区系如何调节肠道的理解 适应性免疫系统。我们的发现将有助于确定抑制或增强维生素A的新策略 对肠道免疫系统进行动员，以治疗感染和炎症。

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 intestinal adaptive immune responses, including the homing of T and B cells to the intestine and immunoglobulin A production. These vitamin A-dependent immune responses depend on specialized intestinal myeloid cells that enzymatically convert the vitamin A derivative retinol to retinoic acid (RA). In the previous project period we unraveled a molecular mechanism by which intestinal myeloid cells acquire retinol. We discovered that serum amyloid A (SAA) proteins – microbiota-inducible epithelial cell proteins – are retinol chaperones that deliver retinol to myeloid cells via the endocytic receptor LRP1 (low density lipoprotein-related receptor 1). We found that this mechanism is essential for the development of intestinal adaptive immunity and for immune protection against pathogenic bacterial infection. This R01 renewal application will build on these findings to further define the biochemical, cell biological, and microbiological mechanisms that regulate retinol delivery to intestinal myeloid cells and thus promote vitamin A-dependent immunity. In Aim 1, we will determine how SAA-retinol complexes are assembled and secreted from intestinal epithelial cells. In Aim 2, we will identify the SAA-LRP1 interface and determine its importance for myeloid cell retinol uptake and vitamin A-dependent immunity. In Aim 3, we will define the role of the intestinal microbiota in regulating myeloid cell retinol acquisition and vitamin A-dependent immunity. These studies will provide mechanistic insight into how vitamin A is mobilized to intestinal immune cells and advance our understanding of how the gut microbiota regulates the intestinal adaptive immune system. Our findings will help identify new strategies for inhibiting or enhancing vitamin A mobilization to the intestinal immune system in order to treat infection and inflammation.