Dataset Information

Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.

ABSTRACT: Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)⁺ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2⁺ monocytes in murine CF lungs drive pathogenic transforming growth factor β (TGF-β) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-β signaling and prevents lung tissue damage. This study identifies CCR2⁺ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.

SUBMITTER: Oz HH

PROVIDER: S-EPMC9833830 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.

Öz Hasan H HH Cheng Ee-Chun EC Di Pietro Caterina C Tebaldi Toma T Biancon Giulia G Zeiss Caroline C Zhang Ping-Xia PX Huang Pamela H PH Esquibies Sofia S SS Britto Clemente J CJ Schupp Jonas C JC Murray Thomas S TS Halene Stephanie S Krause Diane S DS Egan Marie E ME Bruscia Emanuela M EM

Cell reports 20221201 11

Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)<sup>+</sup> monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. He ...[more]

PMID: 36516754

Similar Datasets

Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a complicated pathological cascade process of excessive pulmonary inflammation and alveolar epithelial cell apoptosis that results in respiratory dysfunction and failure. Some cases of ARDS can result in a more severe state of pulmonary fibrosis, referred to as postinjury lung fibrosis. The mortality and incidence rate of ARDS are high, particularly when it leads to continuing alveolar and interstitial fibrosis, which requires urgent treatment and appropriate management. The lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model has been widely implemented for studying ARDS in humans. In our study, we found alterations in the alveolar macrophage (AM) profile in such a mouse model. Specifically, activin-A produced by dominantly recruited AMs (recAMs) was noted to be implicated in the process of post-injury lung fibrosis.MethodsThe ALI animal model in C57BL/6 mice was established via 3.5 mg/kg of LPS intratracheal administration. Single-cell RNA (scRNA) sequencing was used for detailed classification and functional characterization of lung macrophages. Through in vivo experiments, we evaluated the role that activin-A plays in post-injury lung fibrosis in an ALI mouse model using enzyme-linked immunosorbent assay (ELISA), histological staining methods, and immunofluorescence. Through in vitro experiments, we analyzed the effect of activin-A on murine lung epithelial 12 (MLE-12) cells and bone marrow-derived macrophages (BMDMs) using Western blotting (WB), quantitative real-time polymerase chain reaction, RNA sequencing, and immunofluorescence.ResultsOur findings revealed that recAMs replaced tissue-resident alveolar macrophages (TRAMs) as the dominant macrophage population in the setting of ALI. The results of Gene Ontology (GO) analysis suggested that activin-A was associated with wound healing and suppressor of mothers against decapentaplegic (SMAD) protein signaling pathways. Immunofluorescence results revealed that the receptor of activin-A mainly localized to alveolar epithelial cells and macrophages. Subsequently, activin-A was specifically found to drive MLE-12 cells to mesenchymal cell transformation via the transforming growth factor-β (TGF-β)/SMAD signaling. Moreover, the results of transcriptome analysis and WB confirmed that activin-A could enhance the concerted activity of Hippo and TGF-β/SMAD pathways in BMDMs, leading to an increased expression of profibrotic mediator. Moreover, yes-associated protein (YAP) and transcriptional coactivated with PDZ-binding motif (TAZ) proteins were found to drive BMDM activin-A expression, which could generate a positive feedback mechanism that perpetuates fibrosis.ConclusionsOur findings revealed that activin-A is involved in the pathological mechanisms in post-injury lung fibrosis by promoting epithelial-mesenchymal transition (EMT) and the formation of an underlying profibrotic positive feedback loop in recAMs. Activin-A is thus a potential therapeutic target for developing ALI and ALI-associated pulmonary fibrosis therapeutics.

Dataset Information

Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.

Publications

Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets