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Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflamm...

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Autores principales: Zeng, Jianxiong, Xie, Xiaochun, Feng, Xiao-Li, Xu, Ling, Han, Jian-Bao, Yu, Dandan, Zou, Qing-Cui, Liu, Qianjin, Li, Xiaohong, Ma, Guanqin, Li, Ming-Hua, Yao, Yong-Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719059/
https://www.ncbi.nlm.nih.gov/pubmed/34979342
http://dx.doi.org/10.1016/j.ebiom.2021.103803
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author Zeng, Jianxiong
Xie, Xiaochun
Feng, Xiao-Li
Xu, Ling
Han, Jian-Bao
Yu, Dandan
Zou, Qing-Cui
Liu, Qianjin
Li, Xiaohong
Ma, Guanqin
Li, Ming-Hua
Yao, Yong-Gang
author_facet Zeng, Jianxiong
Xie, Xiaochun
Feng, Xiao-Li
Xu, Ling
Han, Jian-Bao
Yu, Dandan
Zou, Qing-Cui
Liu, Qianjin
Li, Xiaohong
Ma, Guanqin
Li, Ming-Hua
Yao, Yong-Gang
author_sort Zeng, Jianxiong
collection PubMed
description BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. METHODS: We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. FINDINGS: We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3(−/−) mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. INTERPRETATION: Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. FUNDING: This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS “Light of West China” Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.).
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spelling pubmed-87190592022-01-03 Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice Zeng, Jianxiong Xie, Xiaochun Feng, Xiao-Li Xu, Ling Han, Jian-Bao Yu, Dandan Zou, Qing-Cui Liu, Qianjin Li, Xiaohong Ma, Guanqin Li, Ming-Hua Yao, Yong-Gang EBioMedicine Article BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. METHODS: We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. FINDINGS: We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3(−/−) mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. INTERPRETATION: Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. FUNDING: This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS “Light of West China” Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.). Elsevier 2021-12-31 /pmc/articles/PMC8719059/ /pubmed/34979342 http://dx.doi.org/10.1016/j.ebiom.2021.103803 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zeng, Jianxiong
Xie, Xiaochun
Feng, Xiao-Li
Xu, Ling
Han, Jian-Bao
Yu, Dandan
Zou, Qing-Cui
Liu, Qianjin
Li, Xiaohong
Ma, Guanqin
Li, Ming-Hua
Yao, Yong-Gang
Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title_full Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title_fullStr Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title_full_unstemmed Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title_short Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
title_sort specific inhibition of the nlrp3 inflammasome suppresses immune overactivation and alleviates covid-19 like pathology in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719059/
https://www.ncbi.nlm.nih.gov/pubmed/34979342
http://dx.doi.org/10.1016/j.ebiom.2021.103803
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