Abstract Rationale Pneumonia is a worldwide public health concern, most often caused by respiratory pathogens that vary in etiology. In addition to heterogenous sources of infection, increased antimicrobial resistance necessitates an improved understanding of host response to lung pathogens. We recently reported that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) limits inflammatory injury, partially mediated by a subset LOX-1-expressing neutrophils. Here, our goal was to distinguish the effects of LOX-1 activity on neutrophils during pneumonia. Methods The cellular distribution of lung LOX-1 was examined using single-cell sequencing. Wild-type mice and mice with a conditional deletion of LOX-1 on neutrophils (LOX-1ΔMrp8) were intratracheally treated with S. pneumoniae, K. pneumoniae, E. coli or PBS for 12-48H. Spectral flow cytometry with intravascular staining was used to determine neutrophil phenotype and their location. LOX-1-dependent impact on infection outcome was determined by bronchoalveolar lavage (BAL) and measurement of cytokines (ELISA), total protein (BCA), and bacterial CFU (blood and lung). Results We previously observed that intratracheal LOX-1 blockade increases pneumonia-induced injury. A comparison of single-cell sequencing datasets showed substantial enrichment of LOX-1 (olr1) mRNA in airspace neutrophils during pneumonia; however, LOX-1 was virtually absent in blood and bone marrow. Interestingly, LOX-1 was inducible on bone marrow neutrophils when exposed to infected BAL fluid ex vivo and is substantially enriched in neutrophils expressing sca-1 and c-kit in the blood and bone marrow, indicating a more progenitor-like phenotype. At baseline, LOX-1 is considerably elevated in lung neutrophils, with a phenotype consistent with reported homeostatic, long-lived neutrophils, including expression of CD101, MHCII, and sca-1 and mitochondrial metabolism. Loss of LOX-1 on neutrophils led to elevated lung injury (BCA, cytokines) and bacteremia with a more prominent influence during S. pneumoniae infection, an effect which may be due to the heterogeneity of neutrophils in response to different pathogens and their location within the airspace or vasculature. Conclusion Our data implicate a unique, immunoregulatory role for LOX-1 on recruited neutrophils that is dependent on the timing, location, and source of infection. These results provide a framework for future research studying the mechanisms connecting neutrophil LOX-1 to lung homeostasis and response to infection. This abstract is funded by: National Heart, Lung, and Blood Institute
Korkmaz et al. (2026) studied this question.