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
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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

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Figure 3

Expression of LOX-1 is induced in epithelial and endothelial cells during pneumonia with no change in surface expression.

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Expression of LOX-1 is induced in epithelial and endothelial cells durin...
To identify the cellular sources of LOX-1, (A) epithelial (7AAD–CD45–EpCAM+) and endothelial (7AAD–CD45–EpCAM–CD31+) cells were isolated by FACS following either elastase (mRNA expression) or dispase (surface expression) digestion of lungs collected from age-matched C57BL/6 mice (n = 3–5 per group) intratracheally treated with saline or E. coli for 24 hours. (B) Olr1 gene expression was determined by RT-qPCR. Sorted cells were further gated into LOX-1+ and LOX-1– by flow cytometry, and (C) total LOX-1+ cells and (D) LOX-1 median fluorescence intensity (MFI) were determined. Data are represented as mean ± SEM with individual data points representative of mice from 1–2 independent experiments. **P < 0.01 for 2-way ANOVA with Holm-Šídák post hoc test.