Imbalance of Ly-6Chi and Ly-6Clo Monocytes/Macrophages Worsens Hyperoxia-Induced Lung Injury and Is Rescued by IFN-γ

Abstract

Inflammation in response to oxygen exposure is a major contributing factor in neonatal lung injury leading to bronchopulmonary dysplasia. Although increased levels of proinflammatory cytokines are seen in airway samples and blood from bronchopulmonary dysplasia patients, the innate immune responses in this common neonatal lung condition have not been well characterized. We previously reported that depletion of murine CD11b-expressing mononuclear phagocytes at birth led to severe acute hyperoxia-induced lung injury (HILI) and significant mortality. In this study, we further define the mononuclear phagocyte populations that are present in the neonatal lung and characterize their responses to hyperoxia exposure. We used myeloid depleter mice (CD11b-DTR and CCR2-DTR) to contrast the effects of depleting different monocyte/macrophage subpopulations on the innate immune response to hyperoxia. Using RNA sequencing and subsequent data analysis, we identified an IFN-γ–mediated role for interstitial monocytes/macrophages in acute HILI, in which decreased IFN-γ expression led to increased disease severity and increased Mmp9 mRNA expression. Importantly, intranasal administration of rIFN-γ largely rescued CD11b-DTR+ mice from severe HILI and decreased Mmp9 mRNA expression in Ly-6Clo and Ly-6Chi interstitial monocyte/macrophages. We conclude that the proinflammatory effects of hyperoxia exposure are, at least in part, because of the modulation of effectors downstream of IFN-γ by pulmonary monocytes/macrophages.

CCR2 Mediates Chronic LPS-Induced Pulmonary Inflammation and Hypoalveolarization in a Murine Model of Bronchopulmonary Dysplasia

“…However, the ExMf response to LPS in CCR2−/− mice was not completely blocked. This finding is in agreement with other reports demonstrating attenuated, but not completely abolished recruitment of exudative macrophages in a murine model of hyperoxia-induced hypoalveolarization ( 40 , 72 ), and non-infectious lung injury model ( 37 ). In the hyperoxia-induced hypoalveolarization model, other resident macrophage populations that become activated upon exposure, specifically Csf1r-expressing monocyte/macrophages, but not neutrophils are key mediators of arrested alveolarization ( 40 ).…”

“…CCL2 is required for hyperoxia-induced alveolar simplification ( 27 ). Further, hyperoxia-induced lung injury and hypoalveolarization and exudative macrophage recruitment are attenuated in CCR2−/− mice ( 40 , 72 ). The inflammatory stimulus during hyperoxic exposure is likely multifaceted.…”

IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death

“… 26 On the other hand, IFN-γ rescued an imbalance of inflammation in lung injury. 29 IFN-γ is necessary for B cell survival in rheumatoid arthritis. 30 IFN-γ is also known to protect cardiac hypertrophy in response to pressure overload and aldosterone infusion.…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…However, depletion of Csf1r-lineage resident alveolar macrophages resulted in a pronounced protection of alveolar development from the impact of hyperoxia exposure, pointing to resident alveolar macrophages as key pathogenic mediators of hyperoxia-driven stunting of postnatal lung development (253). Along similar lines, an imbalance in Ly-6 hi and Ly-6C lo monocytes/macrophages was documented to worsen hyperox-ia-induced lung injury in mouse pups, which could be rescued by ␥-interferon administration (153). Beyond macrophages, Th2 cytokines, typically addressed recently in fibrosis (532) and allergic airway inflammation (322), have also received attention in lung development and BPD.…”