Impaired autophagy, mitochondrial dysfunction, and inflammation in pancreatitis

摘要/摘要 胰腺炎是胰腺外分泌部的一种潜在致死性疾病，其发病机制尚不明确， 有效治疗。过度/未消退的炎症是胰腺炎严重程度的主要决定因素 但其机制尚不清楚。最近在实验和遗传模型中的发现揭示了 受损的自噬和线粒体功能障碍在腺泡细胞损伤驱动中的关键致病作用 胰腺炎;这些途径的紊乱在人类疾病中也很突出。封锁/损害 胰腺自噬启动炎症的遗传模型，如胰腺特异性敲除的关键 自噬介质ATG 5。相反，增强自噬效率（或使线粒体功能正常化） 改善实验性胰腺炎的炎症反应。这些发现有力地表明， 自噬限制胰腺炎的炎症;然而，其潜在机制尚不清楚。 我们假设胰腺炎中自噬受损与炎症之间的一个关键机制是腺泡 细胞线粒体功能障碍;此外，这种机制是由腺泡细胞增加介导的， 线粒体（mt）ROS和mtDNA释放。我们认为这些效应物激活了主要的促炎因子， 途径：NF-κB，触发腺泡细胞中细胞因子/趋化因子的表达，从而启动细胞因子/趋化因子的表达。 炎症反应;巨噬细胞中的DNA敏感cGAS-STING-TBK 1途径，导致产生 和巨噬细胞中的炎性小体活化，导致大量产生IL-1β和IL-2 β。 18.拟议的研究将使用遗传学和药理学方法来阐明这些基因的作用。 途径。将在3个特定目标中检验假设： 1）。确定受损的自噬对线粒体功能障碍和胰腺炎症的影响 胰腺炎的遗传和实验模型。 2）。研究巨噬细胞cGAS-STING-TBK 1通路激活引起的自噬受损， 胰腺炎的遗传和实验模型。 3）。研究（经典）炎性体通路在受损的巨噬细胞活化中的作用。 自噬和线粒体功能障碍。 我们提出的研究将确定受损的自噬和线粒体 巨噬细胞驱动的胰腺炎炎症反应的功能障碍。这些研究将确定分子 这些通路中的靶点可能适合于药物干预以减轻炎症反应， 胰腺炎的反应。

Summary/Abstract Pancreatitis is a potentially fatal disease of exocrine pancreas, with obscure pathogenesis and no specific or efficient treatment available. Excessive/unresolving inflammation is a major determinant of pancreatitis severity but its mechanisms are poorly understood. Recent findings in experimental and genetic models have uncovered key pathogenic roles of impaired autophagy and mitochondrial dysfunction in acinar cell damage driving pancreatitis; disordering of these pathways is also prominent in human disease. Blockade/impairment of pancreatic autophagy initiates inflammation in genetic models, such as pancreas-specific knockout of the key autophagy mediator ATG5. Conversely, enhancing autophagic efficiency (or normalizing mitochondrial function) ameliorates the inflammatory response in experimental pancreatitis. These findings strongly indicate that normal autophagy restricts inflammation in pancreatitis; however, the underlying mechanisms are unknown. We hypothesize that a key mechanism linking impaired autophagy to inflammation in pancreatitis is acinar cell mitochondrial dysfunction; and further, that this mechanism is mediated by the increase in acinar cell mitochondrial (mt)ROS and mtDNA release. We posit that these effectors activate major proinflammatory pathways: NF-κB, triggering the expression of cytokines/chemokines in acinar cells and thus initiating the inflammatory response; the DNA-sensing cGAS-STING-TBK1 pathway in macrophages, resulting in production of type I IFNs; and inflammasome activation in macrophages, resulting in massive production of IL-1β and IL- 18. The proposed studies will use genetic and pharmacologic approaches to elucidate the roles of these pathways. The hypothesis will be tested in 3 Specific Aims: 1). Determine the effects of impaired autophagy on mitochondrial dysfunction and pancreatic inflammation in genetic and experimental models of pancreatitis. 2). Investigate macrophage cGAS-STING-TBK1 pathway activation caused by impaired autophagy in genetic and experimental models of pancreatitis. 3). Investigate the role of (canonical) inflammasome pathway in macrophage activation caused by impaired autophagy and mitochondrial dysfunction. Our proposed studies will determine the mechanisms linking impaired autophagy and mitochondrial dysfunction to macrophage-driven inflammatory response of pancreatitis. The studies will identify molecular targets in these pathways that could be amenable for pharmacologic intervention to alleviate the inflammatory response of pancreatitis.