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J Immunol. 2019 May 1;202(9):2772-2781. doi: 10.4049/jimmunol.1801374. Epub 2019 Apr 3.

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

Author information

1
Division of Pulmonology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA 98105.
2
Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98121; and.
3
Immunology Program, Benaroya Research Institute, Seattle, WA 98101.
4
Immunology Program, Benaroya Research Institute, Seattle, WA 98101 sziegler@benaroyaresearch.org.

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.

PMID:
30944158
DOI:
10.4049/jimmunol.1801374

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