Lectin-like oxidized low-density lipoprotein receptor 1 attenuates pneumonia-induced lung injury
Filiz T. Korkmaz, Anukul T. Shenoy, Elise M. Symer, Lillia A. Baird, Christine V. Odom, Emad I. Arafa, Ernest L. Dimbo, Elim Na, William Molina-Arocho, Matthew Brudner, Theodore J. Standiford, Jawahar L. Mehta, Tatsuya Sawamura, Matthew R. Jones, Joseph P. Mizgerd, Katrina E. Traber, Lee J. Quinton
Filiz T. Korkmaz, Anukul T. Shenoy, Elise M. Symer, Lillia A. Baird, Christine V. Odom, Emad I. Arafa, Ernest L. Dimbo, Elim Na, William Molina-Arocho, Matthew Brudner, Theodore J. Standiford, Jawahar L. Mehta, Tatsuya Sawamura, Matthew R. Jones, Joseph P. Mizgerd, Katrina E. Traber, Lee J. Quinton
View: Text | PDF
Research Article Immunology Inflammation

Lectin-like oxidized low-density lipoprotein receptor 1 attenuates pneumonia-induced lung injury

Abstract

Identifying host factors that contribute to pneumonia incidence and severity are of utmost importance to guiding the development of more effective therapies. Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1, encoded by OLR1) is a scavenger receptor known to promote vascular injury and inflammation, but whether and how LOX-1 functions in the lung are unknown. Here, we provide evidence of substantial accumulation of LOX-1 in the lungs of patients with acute respiratory distress syndrome and in mice with pneumonia. Unlike previously described injurious contributions of LOX-1, we found that LOX-1 is uniquely protective in the pulmonary airspaces, limiting proteinaceous edema and inflammation. We also identified alveolar macrophages and recruited neutrophils as 2 prominent sites of LOX-1 expression in the lungs, whereby macrophages are capable of further induction during pneumonia and neutrophils exhibit a rapid, but heterogenous, elevation of LOX-1 in the infected lung. Blockade of LOX-1 led to dysregulated immune signaling in alveolar macrophages, marked by alterations in activation markers and a concomitant elevation of inflammatory gene networks. However, bone marrow chimeras also suggested a prominent role for neutrophils in LOX-1–mediated lung protection, further supported by LOX-1+ neutrophils exhibiting transcriptional changes consistent with reparative processes. Taken together, this work establishes LOX-1 as a tissue-protective factor in the lungs during pneumonia, possibly mediated by its influence on immune signaling in alveolar macrophages and LOX-1+ airspace neutrophils.

Authors

Filiz T. Korkmaz, Anukul T. Shenoy, Elise M. Symer, Lillia A. Baird, Christine V. Odom, Emad I. Arafa, Ernest L. Dimbo, Elim Na, William Molina-Arocho, Matthew Brudner, Theodore J. Standiford, Jawahar L. Mehta, Tatsuya Sawamura, Matthew R. Jones, Joseph P. Mizgerd, Katrina E. Traber, Lee J. Quinton

×

Figure 4

Airspace macrophages exhibit abundant LOX-1 expression that is further induced with infection.

Options: View larger image (or click on image) Download as PowerPoint
Airspace macrophages exhibit abundant LOX-1 expression that is further i...
(A) To identify which lung cells exhibit the highest expression of LOX-1, we utilized a publicly available single-cell RNA-sequencing data set (31) and our own data set (30) from human and mouse lungs, respectively, to visualize cell-specific Olr1 gene expression (highlighted in purple). (B) To assess recruited monocyte versus resident macrophage LOX-1 expression, age-matched C57BL/6 mice (n = 8) were intratracheally infected with E. coli for 24 hours, and anti-CD45.2 Ab was administered intravenously 3 minutes prior to euthanasia. Flow cytometry was used to measure intra- and extravascular LOX-1 expression on monocytes and macrophages. Alveolar macrophage expression (red histogram) was compared with fluorescence minus one control (FMO; blue dotted line). (C) Immunofluorescence of LOX-1 (red) versus F4/80 (green) was performed on frozen lung sections from mice intratracheally instilled with saline or E. coli for 24 hours (n = 3 per group) (scale bar = 25 μm). (D) To comprehensively assess myeloid LOX-1 expression, flow cytometry was performed on collagenase-digested lungs collected from C57BL/6 mice treated with either saline or E. coli for 24 hours (n = 6–8 per group). Data are represented as mean ± SEM with individual data points representative of mice from 2 independent experiments. ***P < 0.001, *P < 0.05 by 1- or 2-way ANOVA and Holm-Šídák post hoc test.