Regulation of Pulmonary Host Defenses by the Endoplasmic Reticulum Stress Sensor IRE1α

耐甲氧西林金黄色葡萄球菌（MRSA）感染是全球医院获得性感染的主要原因。仅在美国，每年就有大约1400万人感染。这种病原体中抗生素耐药性的增加突出了迫切需要确定新的治疗靶点来治疗MRSA感染。我们最近发现，内质网（ER）应激传感器IRE 1 α是巨噬细胞、中性粒细胞和感染的小鼠脓肿模型中针对MRSA的先天免疫防御的关键组分。我们发现，IRE 1 α通过增强炎症分子的产生来控制巨噬细胞和中性粒细胞的抗菌功能，这些炎症分子包括线粒体活性氧（MitoROS）、中性粒细胞胞外陷阱（NET）和IL-1β，这些是体内解决MRSA感染所必需的。在肺中，ER应激发生在感染、空气污染物吸入和许多肺部疾病如特发性肺纤维化和哮喘的发展过程中。然而，IRE 1 α如何参与肺部疾病的进展和消退尚不清楚。由于肺是一个重要的器官，巨噬细胞和中性粒细胞必须充分调整它们的反应，以确保有效的抗菌功能，而不会过度损伤组织，从而抑制气体交换。因此，研究肺部感染时IRE 1 α介导的应激反应将为了解肺部宿主防御的调节机制提供有价值的见解。该提案的总体目标是阐明IRE 1 α在MRSA感染期间肺宿主防御中的作用。我们的中心假设是感染触发IRE 1 α信号传导，其增强肺先天免疫效应子功能，包括杀菌活性和炎症介质的产生。我们将实现以下目标来验证我们的假设：（1）表征肺巨噬细胞炎症反应对IRE 1 α激活和MitoROS生成的要求，以及（2）阐明IRE 1 α回路是否有助于或阻碍针对肺部MRSA感染的先天性免疫防御。完成这项研究将建立ER应激反应作为肺宿主防御的重要调控网络，并将为进一步研究细胞应激反应与肺部疾病之间的交叉奠定基础。

Methicillin-resistant Staphylococcus aureus (MRSA) infection is the leading cause of hospital-acquired infection worldwide. It causes approximately 14 million infections annually in the United States alone. Increasing antibiotic resistance in this pathogen highlights a compelling need to identify new therapeutic targets to treat MRSA infections. We recently showed that the endoplasmic reticulum (ER) stress sensor, IRE1α, is a key component in innate immune defense against MRSA in macrophages, neutrophils, and in a murine abscess model of infection. We found that IRE1α controls macrophage and neutrophil antimicrobial functions by enhancing production of inflammatory molecules including mitochondrial reactive oxygen species (MitoROS), neutrophil extracellular traps (NETs), and IL-1β, which are essential for resolving MRSA infection in vivo. In the lung, ER stress occurs during infection, air pollutant inhalation and during the development of many pulmonary diseases like Idiopathic Pulmonary Fibrosis and Asthma. However, how IRE1α is involved in progression and resolution of lung diseases is not well understood. Because the lung is a vital organ, macrophages and neutrophils must adequately tune their responses to ensure effective antimicrobial function without excessive tissue damage that could inhibit gas exchange. Therefore, investigation of IRE1α-mediated stress responses during lung infection will lend valuable mechanistic insight into the regulation of pulmonary host defenses. The overarching goal of this proposal is to elucidate the role of IRE1α in pulmonary host defenses during MRSA infection. Our central hypothesis is that infection triggers IRE1α signaling, which enhances lung innate immune effector functions includes bactericidal activity and production of inflammatory mediators. We will accomplish the following Aims to test our hypothesis: (1) Characterize the requirement of IRE1α activation and MitoROS generation to lung macrophage inflammatory responses, and (2) Elucidate whether the IRE1α circuit aids or impedes innate immune defense against pulmonary MRSA infection. Completing this study will establish the ER stress response as an important regulatory network in lung host defense and will lay the groundwork for further studies in the intersection between cellular stress response and lung diseases.