Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses

Abstract

The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1- (IRE1) is associated with lung infections where innate immune cells are drivers for progression and resolution of inflammation. Yet, the role of IRE1 in pulmonary innate immune host defense during acute respiratory infection remains unexplored. Here, we found that activation of IRE1 in infected lungs compromises immunity against methicillin-resistant Staphylococcus aureus (MRSA)-induced primary and secondary pneumonia. Moreover, activation of IRE1 in MRSA-infected lungs and alveolar macrophages (AMs) leads to exacerbated production of inflammatory mediators followed by cell death. Ablation of myeloid IRE1 or global IRE1 inhibition confers protection against MRSA-induced pneumonia with improves survival, bacterial clearance, cytokine reduction, and lung injury. In addition, loss of myeloid IRE1 protects mice against MRSA-induced secondary to influenza pneumonia by promoting AM survival. Thus, activation of IRE1 is detrimental to pneumonia and therefore, it shows potential as a target to control excessive unresolved lung inflammation.