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

Abstract 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)