Impaired interferon-γ signaling promotes the development of silicosis

Peng, Zhouyangfan; Duan, Mingwu; Tang, Yiting; Wu, Jianfeng; Zhao, Kai; Zhong, Yanjun; He, Zhijun; Meng, Jian; Chen, Fangping; Xiao, Xianzhong; Wang, Haichao; Billiar, Timothy R.; Lü, Ben; Fang, Liang

doi:10.1016/j.isci.2022.104647

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…To further validate the above findings in human samples, we reanalyzed published scRNA-seq data for the BALFs derived from three patients with silicosis and two co-workers without silicosis 26 . A total of 22601 cells from five samples were obtained for subsequent analysis.…”

Section: Resultsmentioning

confidence: 99%

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

Kang,

Gu,

Cao

et al. 2024

Preprint

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BackgroundSilicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied.MethodsThe silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR).ResultsWe found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12himacrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12himacrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12himacrophages, highly expressing both pro-inflammatory and pro-fibrotic genes are derived from Ly6c+monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12himacrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12himacrophages in silicosis mice models.ConclusionsOur study suggested that a group of Mmp12himacrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12himacrophages may be a potential therapy target to further halt the progression of silicosis.

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Section: Resultsmentioning

confidence: 99%

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

Kang,

Gu,

Cao

et al. 2024

Preprint

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“…We analyzed publicly available single-cell RNA sequencing (scRNA-seq) data of bronchoalveolar lavage fluid cells, which are obtained from the silicosis patients and their healthy co-workers ( 17 ). We found that the expression of RAB20 genes is markedly decreased in monocytes and macrophages from silicosis patients, while the RAB20 gene expression in T cells (CD3 + ), CD4 + T cells (CD3 + and CD4 + ), CD8 + T cells (CD3 + and CD8 + ), monocytes (CD14 + ), macrophages (CD68 + ), B cells (B220 + ), and hemopoietic stem cells (HSCs, CD34 + ) from silicosis patients was not altered ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

RAB20 deficiency promotes the development of silicosis via NLRP3 inflammasome

Peng

Duan²,

Zhao³

et al. 2022

Front. Immunol.

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Silicosis is a worldwide serious occupational disease that is caused by inhalation of silica crystals. However, little is known about the pathogenesis mechanism of silicosis. We performed single-cell sequencing in bronchoalveolar lavage fluid (BALF) from mine workers with silicosis and their co-workers who did not develop silicosis, and found that the RAB20 deficiency in monocytes/macrophages was strongly linked to the development of silicosis. In the silicosis murine model, RAB20 knockout markedly enhanced the silica crystal-induced pulmonary interstitial fibrosis and respiratory dysfunction. Moreover, this process is strongly accompanied by IL-1β release and NLRP3 activation. In vitro, RAB20 knockout macrophages aggravated the crystalline silica-induced IL-1β release and NLRP3 inflammasome activation partly by increased ratio of crystalline silica/phagosomal areas/volumes to induce lysosomal injury. Thus, these findings provide novel molecular insights into the intricate mechanisms underlying lysosomal protein RAB20 that are necessary for environmental irritant-mediated innate immunity, and shed light on the future development of novel therapy target for the prevention of silicosis.

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“…There are also reports about beneficial, antifibrotic effects on lung fibrosis. For example, in the initial steps of the fibrosis process, cellular-activated pathways dependent on IFNγ inhibit inflammasome formation and inhibit the stability of the integrity phagosomes containing silica, presumably reducing the frustrated phagocytosis [83]. Treatment of IFNγ had a synergic effect on normal and IPF-derived fibroblasts activation and differentiation [84].…”

Section: Modulation Of the Fibrotic Processmentioning

confidence: 99%

Club Cells—A Guardian against Occupational Hazards

Otelea,

Oancea,

Reisz

et al. 2023

Biomedicines

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Club cells have a distinct role in the epithelial repair and defense mechanisms of the lung. After exposure to environmental pollutants, during chronic exposure, the secretion of club cells secretory protein (CCSP) decreases. Exposure to occupational hazards certainly has a role in a large number of interstitial lung diseases. According to the American Thoracic Society and the European Respiratory Society, around 40% of the all interstitial lung disease is attributed to occupational hazards. Some of them are very well characterized (pneumoconiosis, hypersensitivity pneumonitis), whereas others are consequences of acute exposure (e.g., paraquat) or persistent exposure (e.g., isocyanate). The category of vapors, gases, dusts, and fumes (VGDF) has been proven to produce subclinical modifications. The inflammation and altered repair process resulting from the exposure to occupational respiratory hazards create vicious loops of cooperation between epithelial cells, mesenchymal cells, innate defense mechanisms, and immune cells. The secretions of club cells modulate the communication between macrophages, epithelial cells, and fibroblasts mitigating the inflammation and/or reducing the fibrotic process. In this review, we describe the mechanisms by which club cells contribute to the development of interstitial lung diseases and the potential role for club cells as biomarkers for occupational-related fibrosis.

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Impaired interferon-γ signaling promotes the development of silicosis

Cited by 5 publications

References 48 publications

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

RAB20 deficiency promotes the development of silicosis via NLRP3 inflammasome

Club Cells—A Guardian against Occupational Hazards

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