LOX-1 as a protective countermeasure in response to lung infection

Abstract Pneumonia is a leading cause of morbidity and mortality worldwide, due in large part to the onset of acute respiratory distress syndrome (ARDS), for which there is no greater origin. Imbalances of the biological processes controlling immunity and tissue integrity increase the likelihood that lung infections progress to pneumonia, demanding a better understanding of when, where, and how host signals integrate to confer protection. Here we propose the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as a regulatory node for shaping inflammation in the pneumonic lung. While this receptor has well- established roles in promoting vascular injury in patients with atherosclerosis, its function in the lungs is unknown. Our preliminary results from both mice and humans indicate substantial accumulation of LOX-1 in pneumonic lungs. Moreover, our mouse studies reveal that LOX-1 in the airspace compartment, particularly that originating from hematopoietic cells, dampens immunopathology in the infected lung. This contrasts the harmful roles of LOX-1 during cardiovascular disease, implicating the alveolar milieu as a unique niche for LOX-1-dependent tissue fortification. Although LOX-1 has never been investigated in the context of lung infections, we posit that its expression by alveolar macrophages and neutrophils serves as a countermeasure to dampen pneumonia-induced inflammation and maintain tissue integrity. Therefore, we will test the central hypothesis that LOX-1 on airspace myeloid cells bolsters tissue protection in response to lung infection. This will be addressed by pursuing the following 3 aims: Aim 1) Test the hypothesis hematopoietic cellular subsets prominently contribute to LOX-1-driven tissue protection in the infected lung; Aim 2) Test the hypothesis that LOX-1 promotes efferocytosis and repolarization in alveolar macrophages to limit immunopathology during pneumonia; and Aim 3) Test the hypothesis that LOX-1 guides alveolar neutrophils towards an MDSC-like state through altered lipid handling and anti-inflammatory feedback, countering infection-induced injury. Our proposed studies will leverage complementary in vivo and ex vivo approaches in order to reveal basic biological mechanisms of tissue homeostasis during pneumonia, paving the way for novel clinical interventions in patients with or at risk for this disease.