Microcystin-LR ameliorates pulmonary fibrosis via modulating CD206+ M2-like macrophage polarization
Jie Wang1,2, Lizhi Xu1,3, Zou Xiang4
1Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, 210093, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix deposition with limited treatment options. Based on our previous observation, we hypothesized microcystin-leucine arginine (LR), an environmental cyanobacterial toxin, could potentially suppress pulmonary fibrosis. In this study, we first demonstrated that chronic exposure of microcystin-LR by oral for weeks indeed attenuated the pulmonary fibrosis both on bleomycin-induced rat and fluorescein isothiocyanate-induced mouse models. Our data further indicated that treatment with microcystin-LR substantially reduced TGF-β1/Smad signaling in rat pulmonary tissues. The experiments in vitro found that microcystin-LR was capable of blocking epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) through suppressing the differentiation of CD206+ macrophages. Mechanically, microcystin-LR was found to bind to glucose-regulated protein 78 kDa (GRP78) and suppress endoplasmic reticulum unfolded protein response (UPRER) signaling pathways. These events led to the modulation of M2 polarization of macrophages, which eventually contributed to the alleviation of pulmonary fibrosis. Our results revealed a novel mechanism that may account for therapeutic effect of microcystin-LR on IPF.
Insights
Microcystin-LR, a cyanobacterial toxin, was found to suppress pulmonary fibrosis in rat and mouse models. It works by inhibiting key signaling pathways and macrophage differentiation, offering a potential new therapy for idiopathic pulmonary fibrosis (IPF).
Area of Science:
- Toxicology
- Pulmonary Medicine
- Immunology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with limited treatment options.
- Myofibroblast proliferation and extracellular matrix deposition characterize IPF.
- Previous observations suggested microcystin-LR (a cyanobacterial toxin) might suppress fibrosis.
Purpose of the Study:
- To investigate the potential of microcystin-LR as a therapeutic agent for pulmonary fibrosis.
- To elucidate the underlying mechanisms of microcystin-LR's antifibrotic effects.
Main Methods:
- Chronic oral administration of microcystin-LR in bleomycin-induced rat and FITC-induced mouse models.
- Analysis of TGF-β1/Smad signaling in pulmonary tissues.
- In vitro studies on epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT).
- Investigation of microcystin-LR's interaction with GRP78 and UPRER signaling.
Main Results:
- Microcystin-LR treatment attenuated pulmonary fibrosis in both animal models.
- Reduced TGF-β1/Smad signaling was observed in rat pulmonary tissues.
- Microcystin-LR blocked EMT and FMT by suppressing CD206+ macrophage differentiation.
- Microcystin-LR binds GRP78, suppressing UPRER signaling and modulating M2 macrophage polarization.
Conclusions:
- Microcystin-LR demonstrates significant antifibrotic effects in preclinical models of pulmonary fibrosis.
- The mechanism involves GRP78 binding, UPRER suppression, and M2 macrophage polarization modulation.
- Microcystin-LR represents a novel therapeutic candidate for IPF.
