Investigation of LOX-1 as an Immunometabolic Regulator During Lung Infection 2234171

Introduction Pneumonia is the leading cause of infectious disease related death globally. Current treatment relies on antibiotics but is limited by rising resistance and a lack of host-directed therapies. A better understanding of innate mechanisms that restore lung homeostasis is needed. Alveolar macrophages (AMs), regulate pathogen clearance, inflammation, and repair. The scavenger receptor LOX-1 is uniquely expressed on AMs and is upregulated during infection. Previously, we have shown that LOX-1 serves a protective, anti-inflammatory role in the infected airspace, with concomitant changes in genes that regulate AM metabolism, a driver of immune regulation. In this study, we investigate the role of LOX-1 in regulating AM metabolism and inflammatory signaling during lung infection. Methods AMs from healthy mouse lungs were stimulated with bronchoalveolar lavage fluid (BALF) from E. coli—infected mice, ± LOX-1 inhibition, to model the pneumonic airspace. Metabolic function was then assessed using a Seahorse XFe24 analyzer. To complement this, lung lavage cells from infected and uninfected mice were analyzed by flow cytometry with MitoTracker and MitoSOX dyes. Inflammatory signaling was evaluated by RT-qPCR following BALF stimulation. Results LOX-1 inhibition reduced maximal mitochondrial respiration and increased baseline/compensatory glycolysis in AMs following stimulation with infected BALF, indicating a shift from OXPHOS toward glycolysis. In agreement, flow cytometry revealed decreased MMP in LOX-1 inhibited AMs during lung infection. RT-qPCR of BALF-stimulated macrophages showed increased CXCL2 and IL6 expression, suggesting LOX-1 modulates inflammatory signaling, potentially via metabolic changes. Conclusion LOX-1 promotes mitochondrial respiration and suppresses excessive inflammatory signaling in AMs, highlighting a role in balancing pathogen clearance with resolution of inflammation. These findings suggest LOX-1 as a potential target for host-directed therapies in pneumonia. Funding Source This work was supported by a University of Iowa Startup Grant and NIH/NHLBI R00HL159258 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)