Assistant Professor University of Iowa Iowa City, Iowa, United States
Disclosure(s):
Filiz Korkmaz, PhD: No financial relationships to disclose
Introduction/Rationale: Pneumonia is a worldwide public health concern, necessitating 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 alveolar macrophages (AMs). While oxidized low-density lipoprotein (oxLDL), the primary ligand for LOX-1, elicits inflammation in extrapulmonary macrophages, it is unknown whether oxLDL or other LOX-1 ligands alter AM function, thereby regulating the host response to lung infection.
Methods: Primary AMs or MH-S cells were cultured with oxLDL or apoptotic cells (± anti-LOX-1 or control IgG) to determine primary outcomes and, subsequently, LPS or GFP-labeled E. coli to determine secondary outcomes. WT mice were treated intranasally with oxLDL (± anti-LOX-1 or control IgG) for 24H or after one week, infected with E. coli. WT mice were treated intratracheally (± anti-LOX-1 or control IgG) with apoptotic cells or GFP-labeled E. coli to determine the impact of LOX-1 on efferocytosis or phagocytosis, respectively. Outcomes were measured by live-cell imaging, flow cytometry, RT-qPCR or ELISA.
Results: Earlier work showed that LOX-1 limits injury and inflammation during pneumonia, potentially via AMs. Here, we found that LOX-1 promotes efferocytosis, while limiting phagocytosis in AMs. Moreover, pre-stimulation of AMs with oxLDL reduced iNOS and IL-1B expression in response to LPS or E. coli, while promoting IL-6 and CXCL2 expression. Arginase-1, while suppressed in AMs, was more highly expressed in neutrophils following administration of oxLDL and infection with E. coli, independent of LOX-1.
Conclusion: LOX-1 has emerged as a unique immunoregulatory receptor in the lungs during infection. Our data show that this likely occurs through increased AM efferocytosis and oxLDL-dependent regulation of inflammatory factors, such as iNOS. Future studies will further interrogate LOX-1-dependent and independent mechanisms of protection against lung injury.
