Macrophage-derived exosomes attenuate fibrosis in airway epithelial cells through delivery of antifibrotic miR-142-3p

Abstract

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown.MethodsTwo independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from 19 patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription–PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung fibroblasts.ResultsExosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p<0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor β receptor 1 (TGFβ-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGFβ-R1 by miR-142-3p transfer in target cells.DiscussionOur results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142–3 p to alveolar epithelial cells and lung fibroblasts.

Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis

“…Emerging evidence had indicated exosomes, the paracrine signal mediators, impacted the progression of fibrotic diseases by transferring anti-fibrotic or pro-fibrotic miRNAs to target cells and affected pathological fibrogenesis [ 50 ]. One of the major challenges for synthetic miRNAs was quickly degraded by the high activity of ribonuclease in plasma, but exosome would protect miRNAs from degradation [ 51 , 52 ].…”

Role of extracellular vesicles in chronic lung disease

“…111 A further study by the group showed strong indications that upregulated miR-142-3p, derived from sputum and plasma exosomes of patients with IPF, were of macrophage origin. 110 Guiot et al 110 also found that over expression of miR-142-3p could reduce expression of TGFβ-R1 and ultimately have an antifibrotic effect.…”

Diagnostic and Therapeutic Applications of Extracellular Vesicles in Interstitial Lung Diseases

“…MiR-144-3p and miR-142-3p also inhibit phosphorylation of the SMAD2 protein in a mouse bleomycin-induced lung injury model [ 21 ]. Moreover, macrophage-derived EVs downregulate the expression of TGFβ receptor 1 (TGFβ-R1) and profibrotic genes in lung epithelial cells and lung fibroblasts through miR-142-3p [ 73 ]. Others showed that IL-1β activation on lung fibroblasts stimulated EV-associated prostaglandin E2 (PGE2) production.…”

“…For example, the neutrophil cell line (HL-60) secretes EVs containing miR-1343 that can be taken up by alveolar epithelial cells and lung fibroblasts, further inhibiting TGFβ, a major profibrotic regulatory signaling pathway modulator [ 97 ]. Macrophages are another source of EVs that contain miR-142-3p, which inhibits a profibrotic activation in epithelial cells and lung fibroblasts by downregulating TGFβRI [ 73 ]. The EVs from IL-1β activated human lung fibroblasts contained PGE2 that inhibited myofibroblast differentiation and collagen production, implicating their antifibrotic properties for in vivo testing [ 74 ].…”