Fibrotic lung disease inhibits immune responses to staphylococcal pneumonia via impaired neutrophil and macrophage function
Helen I. Warheit-Niemi, … , David N. O’Dwyer, Bethany B. Moore
Helen I. Warheit-Niemi, … , David N. O’Dwyer, Bethany B. Moore
Published January 6, 2022
Citation Information: JCI Insight. 2022;7(4):e152690. https://doi.org/10.1172/jci.insight.152690.
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Research Article Immunology Pulmonology

Fibrotic lung disease inhibits immune responses to staphylococcal pneumonia via impaired neutrophil and macrophage function

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized patients with IPF. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like humans with IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared with uninfected fibrotic mice. We determine that fibrosis conferred a defect in MRSA clearance compared with nonfibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibited neutrophil intracellular killing of MRSA through impaired neutrophil elastase release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments of antimicrobial responses upon pulmonary fibrosis development, and our findings suggest a possible mechanism for why patients with IPF are at greater risk of morbidity and mortality related to infection.

Authors

Helen I. Warheit-Niemi, Summer J. Edwards, Shuvasree SenGupta, Carole A. Parent, Xiaofeng Zhou, David N. O’Dwyer, Bethany B. Moore

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Figure 6

Fibrosis inhibits NE release, ROS and H2O2 production, and neutrophil chemotaxis.

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Fibrosis inhibits NE release, ROS and H2O2 production, and neutrophil ch...
(A) NE release by bone marrow neutrophils (n = 8). Cells from 2–3 mice per group. Data are representative of 2 independent experiments. (B) ROS production by bone marrow neutrophils (saline n = 4, bleomycin n = 3, saline + MRSA n = 8, bleomycin + MRSA n = 6). Cells from 4–6 mice per group. Data from 2 combined experiments. (C) H2O2 production by bone marrow neutrophils (uninfected n = 6, saline + MRSA n = 12, bleomycin + MRSA n = 11). Cells from 2–3 mice per group. Data are representative of 2 independent experiments. (A–C) Dots represent technical replicates of pooled cells. Statistical analysis by 1-way ANOVA with Tukey’s multiple comparisons. Data represent the means ± SD. **P < 0.01, ***P < 0.001, ****P < 0.0001. (D) Under agarose chemotaxis assay measuring bone marrow neutrophil migration toward formyl peptide receptor (FPR) agonist WKYMVm (100 nM) for 3 hours with 20-second time intervals. Representative endpoint images of the migrating neutrophils from saline or bleomycin-treated mice. Five out of 6 experiments performed showed inhibited migration in neutrophils from fibrotic mice compared with neutrophils from nonfibrotic mice, while 1 out of 6 experiments showed the opposite effect. (E and F) Bone marrow neutrophils from saline- and bleomycin-treated mice were allowed to migrate under agarose toward WKYMVm (100 nM) for 1.5 to 4 hours. Plots showing the number of neutrophils that left the well (E) and distance traveled by the chemotaxing neutrophils (F) are presented. Data represent mean ± SEM from 4–5 independent experiments. Data points with identical shape represent data collected from the same experiment with matched migration time. *P < 0.05 when compared with saline group (paired 2-tailed Student’s t test).