METABOLIC CONTROL OF EPITHELIAL AUTOPHAGY DURING INFLAMMATION

 描述(申请人提供)：胃肠上皮是对抗无处不在的肠腔抗原的主要细胞屏障，并作为微生物病原体和共生生物的天然免疫感受器积极参与。因此，肠道上皮定义了宿主-微生物区系相互作用和肠道内环境稳定的中心界面。基于它们与缺氧肠腔的并列，肠上皮细胞在低氧压微环境中发挥生理学作用，并表现出独特的适应性氧合特征。在与炎症性肠病(IBD)相关的活动性炎症中，粘膜代谢发生了深刻的变化，导致营养和氧气耗竭或缺氧。在哺乳动物细胞中，缺氧诱导的适应性转录程序主要通过缺氧诱导因子(HIF)复合体介导。HIF在协调上皮基因调控中的保护作用已经被确定，转录反应被整合到特定的支持屏障功能和对低氧微环境的适应。HIF靶点的全基因组图谱强调了与宿主-微生物代谢轴有关的两条新的低氧调节途径：促进时空ATP缓冲和屏障能量学的肌酸激酶穿梭，以及选择性自噬。自噬是一种高度保守的分解代谢途径，协调细胞和组织对代谢应激源和感染的不同方面的反应，最近被认为是消除入侵细菌(异种吞噬)的关键作用。重要的是，上皮性自噬通路在IBD中调节失调。虽然大量的努力集中在识别核心自噬成分上，但在转录水平上对上皮自噬的调控特征很差。特别是，关于规范自噬基因反应的协调以及这些反应如何调节细胞内病原体的异噬捕获，人们知之甚少。最近，线粒体选择性自噬(有丝分裂)与感染性疾病之间的基本联系已被证实，线粒体能量学已被证明显著影响小鼠结肠炎的临床过程。我们正在进行的研究已经确定了一组丝裂原(BNIP3L)和异源(NOD2)基因，它们都是由上皮细胞中的缺氧和HIF稳定诱导的。初步工作表明，入侵细菌在低氧条件下以HIF依赖的方式被异种吞噬有效地靶向。上皮性HIF缺陷小鼠在急性细菌攻击后表现出更多的细菌传播和疾病活动。此外，HIF介导的肌酸代谢的增强和上皮生物能量学在小鼠肠道炎症模型中被证明具有保护作用。基于这些观察，我们假设上皮HIF通路以细胞自主的方式收敛，以协调线粒体和代谢稳态与侵入性微生物检测。

 DESCRIPTION (provided by applicant): The gastrointestinal epithelium comprises the primary cellular barrier against omnipresent luminal antigens, and actively participates as an innate immune sensor of microbial pathogens and commensal organisms. As such, intestinal epithelia define the central interface for host-microbiota interactions and intestinal homeostasis. Based on their juxtaposition to the anoxic gut lumen, intestinal epithelial cells function physiologicall in a low- oxygen-tension microenvironment, and exhibit a uniquely adaptive oxygenation profile. In active inflammation associated with inflammatory bowel disease (IBD), mucosal metabolism is profoundly altered, resulting in nutrient and oxygen depletion or hypoxia. Adaptive transcriptional programs elicited by oxygen deprivation in mammalian cells are mediated primarily through the hypoxia-inducible factor (HIF) complex. A protective role for HIF in orchestrating epithelial gene regulation has been identified, with transcriptional responses integrated to specifically support barrier function and adaptations to the hypoxic microenvironment. Genome-wide profiling of HIF target loci highlighted two novel hypoxia-regulated pathways implicated in the host-microbial metabolic axis: the creatine kinase shuttle that promotes spatiotemporal ATP buffering and barrier energetics, and selective autophagy. Autophagy, a highly conserved catabolic pathway, coordinates diverse aspects of cellular and organismal responses to metabolic stressors and infection and has recently been ascribed a key role in the elimination of invasive bacteria (xenophagy). Importantly, epithelial autophagic pathways are dysregulated in IBD. While significant efforts have focused on identification of core autophagy components, regulation of epithelial autophagy at the transcriptional level is poorly characterized. In particular, little is known regarding the coordination of canonical autophagy gene responses and how these modulate xenophagic capture of intracellular pathogens. A fundamental link between selective autophagy of damaged mitochondria (mitophagy) and infectious disease has recently been established, and mitochondrial energetics have been shown to significantly influence the clinical course of murine colitis. Our ongoing studies have identified a cohort of both mitophagic (BNIP3L) and xenophagic (NOD2) genes that are induced by hypoxia and HIF- stabilization in epithelia. Preliminary work has revealed that invasive bacteria are effectively targeted by xenophagy under hypoxic conditions in a HIF-dependent manner. Epithelial HIF-deficient mice demonstrate increased bacterial dissemination and disease activity following acute bacterial challenge. Moreover, augmentation of HIF-mediated creatine metabolism and epithelial bioenergetics proved protective in mouse models of intestinal inflammation. Based on these observations, we hypothesize that epithelial HIF pathways converge in a cell autonomous manner to coordinate mitochondrial and metabolic homeostasis with invasive microbe detection.