Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia

Abstract Pneumonia is the leading cause of infection-related deaths worldwide, a fact that is set to rise exponentially with the SARS-CoV2 pandemic. Recovery from pneumonia requires both clearance of the pathogen and resolution of infection, the latter of which is critical to resume normal lung function. While both processes are important to host health, there is vastly less known about the mechanisms that regulate resistance to and resolution of tissue injury during pneumonia, representing a large knowledge gap in our understanding of the biology of the lung and its repair processes. Here, we propose that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) modulates acute pulmonary inflammation in way that promotes resolution through reprogramming of leukocyte response. LOX-1 is a class E scavenger receptor, primarily known for its role in promoting vascular inflammation during atherosclerosis. In direct contrast, our data suggests that LOX-1 has a unique function in the lung, where it prevents edematous lung injury and inflammation, independent of bacterial clearance in murine models of Escherichia coli and Streptococcus pneumoniae pneumonia. Moreover, LOX-1 and its major ligand oxidized low-density lipoprotein (oxLDL) are elevated in patients with ARDS as a result of a confirmed diagnosis of pneumonia. Analysis of the cellular expression of LOX-1 in the lung revealed that alveolar macrophages and recruited (airspace) neutrophils are uniquely enriched for LOX-1 expression. Hematopoietic cells are also likely sources of LOX-1-dependent protection, as LOX-1-/- (WT recipient) chimeras are significantly more protected from injury than WT (LOX-1-/- recipient) chimeras during pneumonia. Assessment of the specific effects of LOX-1 inhibition on alveolar macrophages demonstrated that with inhibition macrophages are skewed towards inflammation and exhibit metabolic changes associated with increased glycolysis and lower fatty acid oxidation consistent with inflammatory macrophages. Moreover, we discovered that recruited neutrophils differ in their expression of LOX-1, where about half of neutrophils are positive during infection. Curiously, we also found phenotypic differences associated with LOX-1+ neutrophils that suggest increased cholesterol metabolism, which may uniquely promote tissue resolution. Taken together, leukocytes are an important source of LOX-1 and are likely responsible for LOX-1-dependent protection during pneumonia. However, whether and how LOX-1 elicits its protective effects on leukocytes is not known. Thus, we propose a central hypothesis that LOX-1 signaling evokes tissue-protective mechanisms in leukocytes (K99), that are associated with metabolic changes consistent with reduced inflammation and increased tissue recovery (R00). Results from our investigations will be the first to elucidate how LOX-1 is regulated at the transcriptional and metabolic level in the unique microenvironment of the lung, where it likely facilitates recovery from pneumonia and lung homeostasis.