Impaired autophagy, mitochondrial dysfunction, and inflammation in pancreatitis

摘要/摘要 胰腺炎是一种潜在的致命性外分泌胰腺疾病，发病机制不明，无特异性或特异性。 提供有效的治疗方法。过度/未消退的炎症是胰腺炎严重程度的主要决定因素 但人们对其机制知之甚少。最近在实验和遗传模型中的发现揭示了 自噬受损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 胰腺自噬在遗传模型中引发炎症，例如胰腺特异的关键基因敲除 自噬介体ATG5。相反，提高自噬效率(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，正常 自噬抑制了胰腺炎的炎症反应；然而，其潜在的机制尚不清楚。 我们假设，将自噬受损与胰腺炎炎症联系起来的关键机制是腺泡。 细胞线粒体功能障碍；而且，这一机制是由腺泡细胞的增加所介导的 线粒体(MT)ROS和mtDNA释放。我们假设这些效应器激活了主要的促炎因子 途径：核因子-κB，触发细胞因子/趋化因子在腺泡细胞中的表达，从而启动 炎症反应；巨噬细胞中DNA敏感的cGAS-STING-TBK1通路，导致产生 I型干扰素；巨噬细胞炎性小体激活，导致IL-1β和IL-1的大量产生 18.拟议的研究将使用遗传学和药理学方法来阐明这些因素的作用 小路。这一假设将在3个具体目标上进行检验： 1)。确定自噬受损对线粒体功能障碍和胰腺炎症的影响 在胰腺炎的遗传和实验模型中。 2)。自噬受损引起巨噬细胞cGAS-STING-TBK1途径活化的研究 胰腺炎的遗传和实验模型。 3)。探讨(典型)炎性小体途径在受损的巨噬细胞激活中的作用 自噬和线粒体功能障碍。 我们提出的研究将确定自噬受损和线粒体之间的联系机制。 胰腺炎巨噬细胞驱动的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以通过药物干预来减轻炎症 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.