Journal
EXPERIMENTAL CELL RESEARCH
Volume 362, Issue 2, Pages 489-497Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2017.12.013
Keywords
NLRP3 inflammasome; Epithelial to mesenchymal transition; Silica
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Funding
- National Natural Science Foundation of China [81273571]
- Jiangsu Clinical Research Center for Respiratory Diseases project [BL2012012]
- Jiangsu Provincial Key Medical Discipline (Laboratory) [ZDXKA2016006]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [JX10231802]
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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-1 beta (IL-1 beta) 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-kappa B 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.
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