Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome
The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; h...
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doaj-65b8aa6978a243ed9aec7d7a6fb541372020-11-25T00:13:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-08-01910.3389/fimmu.2018.01920379530Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 InflammasomeWei-Ting Wong0Lan-Hui Li1Yerra Koteswara Rao2Shih-Ping Yang3Shu-Meng Cheng4Wen-Yu Lin5Cheng-Chung Cheng6Ann Chen7Kuo-Feng Hua8Kuo-Feng Hua9Kuo-Feng Hua10National Defense Medical Center, Graduate Institute of Life Sciences, Taipei, TaiwanDepartment of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, TaiwanDepartment of Biotechnology and Animal Science, National Ilan University, Yilan City, TaiwanDivision of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDepartment of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDepartment of Biotechnology and Animal Science, National Ilan University, Yilan City, TaiwanDepartment of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDepartment of Medical Research, China Medical University Hospital, Taichung, TaiwanThe NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.https://www.frontiersin.org/article/10.3389/fimmu.2018.01920/fullCarvedilolNLRP3 inflammasomeautophagymitochondriaperitonitis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei-Ting Wong Lan-Hui Li Yerra Koteswara Rao Shih-Ping Yang Shu-Meng Cheng Wen-Yu Lin Cheng-Chung Cheng Ann Chen Kuo-Feng Hua Kuo-Feng Hua Kuo-Feng Hua |
spellingShingle |
Wei-Ting Wong Lan-Hui Li Yerra Koteswara Rao Shih-Ping Yang Shu-Meng Cheng Wen-Yu Lin Cheng-Chung Cheng Ann Chen Kuo-Feng Hua Kuo-Feng Hua Kuo-Feng Hua Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome Frontiers in Immunology Carvedilol NLRP3 inflammasome autophagy mitochondria peritonitis |
author_facet |
Wei-Ting Wong Lan-Hui Li Yerra Koteswara Rao Shih-Ping Yang Shu-Meng Cheng Wen-Yu Lin Cheng-Chung Cheng Ann Chen Kuo-Feng Hua Kuo-Feng Hua Kuo-Feng Hua |
author_sort |
Wei-Ting Wong |
title |
Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome |
title_short |
Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome |
title_full |
Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome |
title_fullStr |
Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome |
title_full_unstemmed |
Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome |
title_sort |
repositioning of the β-blocker carvedilol as a novel autophagy inducer that inhibits the nlrp3 inflammasome |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-08-01 |
description |
The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications. |
topic |
Carvedilol NLRP3 inflammasome autophagy mitochondria peritonitis |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01920/full |
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