Mitochondrial Mechanisms Promoting Innate and Intestinal Immunity

项目摘要/摘要：炎症性肠病(IBD)的主要特征是调节失调 细胞因子和抗微生物反应。与生俱来的机制是主机对 微生物以及由此产生的细胞因子和抗菌素反应需要仔细平衡。线粒体 这些通路在这些先天反应和线粒体的失调中起着关键作用。 机制在IBD发病机制中的作用已得到越来越多的认识。对线粒体的关注 IBD的调节失调主要发生在上皮细胞。然而，线粒体对先天的贡献 免疫结果通过各种机制，包括代谢途径，活性氧物种， 与内质网(ER)通讯，线粒体DNA(MtDNA)释放。&gt；240的 IBD相关基因座中的许多基因调节宿主的先天反应和线粒体 通过直接和间接机制发挥作用。因此，一旦人类巨噬细胞与 微生物产品，我们已经发现了调节糖酵解进而调节巨噬细胞的IBD相关基因 极化、线粒体呼吸链和mtROS，以及内质网应激。我们进一步发现在人类身上 一系列模式识别受体(PRR)配体刺激巨噬细胞，释放mtDNA 随着cGAS-STING通路的激活，cGAS-STING显著增加。然后是cGAS-刺痛途径 其作用是促进许多PRR的反应。我们有初步数据显示至少有一种IBD- 部分定位于线粒体的相关基因LACC1调节PRR诱导的 CGAS-STING途径，进而，下游，PRR启动下游结果。我们假设 CGAS-STING通路通过多种途径放大多种PRR的反应 细胞内机制，这种调节的阈值在肠道易感性中很重要 炎症，并可能在肠道炎症的情况下作为治疗靶点，而IBD- 相关的基因变异调节这些结果，从而影响关键的先天免疫结果。 相关性：这些人类细胞和小鼠的联合研究将提供对线粒体的洞察 巨噬细胞关键结果的调节机制，这些机制在 IBD患者和IBD风险变异的背景下，以及这些机制可能如何在 肠道炎症以改善体内转归。这些综合性和机械性的研究 将为进一步的研究奠定基础，以治疗性地针对跨 先天免疫反应，从而恢复先天免疫失调。

Project Summary/Abstract: Inflammatory bowel disease (IBD) is largely characterized by dysregulated cytokines and antimicrobial responses. Innate mechanisms are the initiating drives of host responses to microbes and the resulting cytokine and antimicrobial responses need to be carefully balanced. Mitochondrial pathways play a key role in mediating these innate responses and a dysregulation in mitochondrial mechanisms has been increasingly recognized to play a role in IBD. The focus on the mitochondrial dysregulation in IBD has been predominantly in epithelial cells. However, mitochondria contribute to innate immune outcomes through a variety of mechanisms, including metabolic pathways, reactive oxygen species, communication with the endoplasmic reticulum (ER), and mitochondrial DNA (mtDNA) release. Of the >240 IBD-associated loci a number of genes within these loci modulate host innate responses and mitochondrial function through both direct and indirect mechanisms. As such, upon encounter of human macrophages with microbial products, we have found IBD-associated genes that regulate glycolysis and in turn macrophage polarization, the mitochondrial respiratory chain and mtROS, and ER stress. We further find that upon human macrophage stimulation by a range of pattern recognition receptor (PRR) ligands, release of mtDNA is dramatically increased along with activation of the cGAS- STING pathway. The cGAS-STING pathway then serves to promote responses across the many PRRs. We have preliminary data that at least one IBD- associated gene which partially localizes to the mitochondria, LACC1, modulates PRR-induced activation of the cGAS-STING pathway, and in turn, downstream PRR-initiated downstream outcomes. We hypothesize that the cGAS-STING pathway amplifies responses across a broad range of PRRs through a variety of intracellular mechanisms, that the threshold of this regulation is important in susceptibility to intestinal inflammation and might be therapeutically targeted under conditions of intestinal inflammation, and that IBD- associated geneticvariants regulate these outcomes, thereby influencing key innate immune outcomes. Relevance: These combined human cell and mouse studies will provide insight into mitochondrial mechanisms regulating key outcomes in macrophages, the manner in which these mechanisms are altered in IBD patients and in the context of IBD risk variants, and how these mechanisms might be modulated during intestinal inflammation in order to improve outcomes in vivo. These comprehensive and mechanistic studies will establish a foundation for additional studies to therapeutically target mitochondrialpathways shared across innate immune responses so as to restore innate immune dysregulation.