NLRP3 inflammasome inhibition attenuates silica-induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells.

Abstract

Silicosis is an incurable and progressive lung disease characterized by chronic inflammation and fibroblasts accumulation. Studies have indicated a vital role for epithelial-mesenchymal transition (EMT) in fibroblasts accumulation. NLRP3 inflammasome is a critical mediator of inflammation in response to a wide range of stimuli (including silica particles), and plays an important role in many respiratory diseases. However, whether NLRP3 inflammasome regulates silica-induced EMT remains unknown. Our results showed that silica induced EMT in human bronchial epithelial cells (16HBE cells) in a dose- and time-dependent manner. Meanwhile, silica persistently activated NLRP3 inflammasome as indicated by continuously elevated extracellular levels of interleukin-1β (IL-1β) and IL-18. NLRP3 inflammasome inhibition by short hairpin RNA (shRNA)-mediated knockdown of NLRP3, selective inhibitor MCC950, and caspase-1 inhibitor Z-YVAD-FMK attenuated silica-induced EMT. Western blot analysis indicated that TAK1-MAPK-Snail/NF-κB pathway involved NLRP3 inflammasome-mediated EMT. Moreover, pirfenidone, a commercially and clinically available drug approved for treating idiopathic pulmonary fibrosis (IPF), effectively suppressed silica-induced EMT of 16HBE cells in line with NLRP3 inflammasome inhibition. Collectively, our results indicate that NLRP3 inflammasome is a promising target for blocking or retarding EMT-mediated fibrosis in pulmonary silicosis. On basis of this mechanism, pirfenidone might be a potential drug for the treatment of silicosis.

• Authors: Xiang Li, Xiaopei Yan, Yanli Wang, Jingjing Wang, Fang Zhou, Hong Wang, Weiping Xie, Hui Kong
• Journal: Experimental cell research (Exp Cell Res) Vol. 362 Issue 2 Pg. 489-497 (01 15 2018) ISSN: 1090-2422 [Electronic] United States
• PMID: 29258746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• Interleukin-1beta
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• RNA, Small Interfering
• Reactive Oxygen Species
• Silicon Dioxide

Topics

• Bronchi (drug effects, metabolism, pathology)
• Epithelial Cells (metabolism)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Fibroblasts (drug effects)
• Humans
• Inflammasomes (genetics)
• Inflammation (chemically induced, genetics, pathology)
• Interleukin-1beta (genetics)
• Lung (drug effects, pathology)
• NF-kappa B (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Silicon Dioxide (toxicity)
• Silicosis (genetics, physiopathology)