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。仅在美国每年就造成约 1400 万例感染。这种病原体的抗生素耐药性不断增加，凸显了寻找新的治疗靶点来治疗 MRSA 感染的迫切需要。我们最近表明，内质网 (ER) 应激传感器 IRE1α 是巨噬细胞、中性粒细胞和小鼠脓肿感染模型中针对 MRSA 的先天免疫防御的关键组成部分。我们发现IRE1α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，包括线粒体活性氧（MitoROS）、中性粒细胞胞外陷阱（NET）和IL-1β，这些分子对于解决体内MRSA感染至关重要。在肺部，内质网应激发生在感染、空气污染物吸入以及许多肺部疾病（如特发性肺纤维化和哮喘）的发展过程中。然而，IRE1α 如何参与肺部疾病的进展和缓解尚不清楚。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其反应，以确保有效的抗菌功能，而不会造成过度的组织损伤，从而抑制气体交换。因此，对肺部感染期间 IRE1α 介导的应激反应的研究将为肺部宿主防御的调节提供有价值的机制见解。该提案的首要目标是阐明 IRE1α 在 MRSA 感染期间肺部宿主防御中的作用。我们的中心假设是感染触发 IRE1α 信号传导，从而增强肺部先天免疫效应功能，包括杀菌活性和炎症介质的产生。我们将实现以下目标来检验我们的假设：(1) 描述 IRE1α 激活和 MitoROS 生成对肺巨噬细胞炎症反应的要求，以及 (2) 阐明 IRE1α 回路是否有助于或阻碍针对肺部 MRSA 感染的先天免疫防御。完成这项研究将把内质网应激反应确立为肺宿主防御的重要调节网络，并将为进一步研究细胞应激反应与肺部疾病之间的交叉关系奠定基础。

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.