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Circulating miR-378a-3p attenuates pulmonary inflammation and fibrosis via BAT-lung crosstalk
Rui He1,2, Xuemin Peng1,2, Ruping Pan3
1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Jiefang Road 1095, Wuhan, 430030, Hubei Province, China.
Abstract:
Pulmonary fibrosis (PF) arises from persistent fibroblast activation and inflammation. Although microRNAs (miRNAs) are promising antifibrotic agents, the contribution of adipose-derived circulating miRNAs to PF remains unclear. Here, we identify brown adipose tissue (BAT) as a major source of exosomal miR-378a-3p that counteracts bleomycin (BLM)-induced PF. In fibrotic mice, BAT activity and circulating exosomal miR-378a-3p were reduced. Activating BAT by cold exposure or β3-adrenergic stimulation increased circulating and pulmonary miR-378a-3p and attenuated collagen deposition and inflammatory infiltration. Adipocyte-specific deletion of miR-378a-3p exacerbated lung inflammation and fibrosis, whereas lung-targeted overexpression of miR-378a-3p or intravenous delivery of BAT-derived exosomes enriched for miR-378a-3p ameliorated disease. Inhibition of exosome release from BAT lowered circulating miR-378a-3p and blunted the anti-fibrotic benefits of BAT activation, supporting a BAT-to-lung transfer mechanism. Mechanistically, miR-378a-3p targets Itga5 to suppress FAK-PI3K-AKT signaling and limiting fibroblast activation, while simultaneously suppressing macrophage inflammatory responses by targeting Fstl1 and suppressing NF-κB activation. Collectively, these findings identify miR-378a-3p as a BAT-derived signaling molecule with dual anti-inflammatory and anti-fibrotic effects in pulmonary fibrosis, expanding the pathophysiological scope of BAT-mediated inter-organ communication to lung disease.
Insights
Brown adipose tissue (BAT) releases exosomal miR-378a-3p, a microRNA that combats pulmonary fibrosis (PF). Activating BAT boosts miR-378a-3p, reducing lung inflammation and fibrosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Physiology
Background:
- Pulmonary fibrosis (PF) involves persistent fibroblast activation and inflammation.
- MicroRNAs (miRNAs) show potential as antifibrotic agents, but their role in PF via adipose tissue is unknown.
- Brown adipose tissue (BAT) is explored for its contribution to circulating miRNAs in PF.
Purpose of the Study:
- To investigate the role of adipose-derived circulating miRNAs in pulmonary fibrosis.
- To identify specific miRNAs from BAT that may counteract PF.
- To elucidate the mechanism of BAT-derived miRNA action in lung disease.
Main Methods:
- Utilized mouse models of bleomycin (BLM)-induced PF.
- Assessed BAT activity, circulating exosomal miR-378a-3p levels, and lung pathology.
- Manipulated miR-378a-3p levels in adipocytes and lungs, and used BAT-derived exosomes.
- Investigated molecular targets of miR-378a-3p in fibroblast and macrophage signaling pathways.
Main Results:
- BAT activity and exosomal miR-378a-3p were reduced in fibrotic mice.
- Cold exposure or β3-adrenergic stimulation of BAT increased circulating/pulmonary miR-378a-3p, reducing fibrosis.
- Adipocyte-specific miR-378a-3p deletion worsened PF; lung overexpression or exosome delivery ameliorated it.
- miR-378a-3p targets Itga5 (suppressing fibroblast activation via FAK-PI3K-AKT) and Fstl1 (suppressing macrophage NF-κB activation).
Conclusions:
- BAT is a significant source of exosomal miR-378a-3p, acting as an antifibrotic factor.
- miR-378a-3p exerts dual anti-inflammatory and anti-fibrotic effects in PF.
- BAT-to-lung communication via exosomal miR-378a-3p is a novel mechanism in pulmonary fibrosis treatment.
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