tetano
Editor, Senior Moderator
EBioMedicine
. 2021 Dec 31;75:103803.
doi: 10.1016/j.ebiom.2021.103803. Online ahead of print.
Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
Jianxiong Zeng[SUP] 1 [/SUP], Xiaochun Xie[SUP] 2 [/SUP], Xiao-Li Feng[SUP] 3 [/SUP], Ling Xu[SUP] 4 [/SUP], Jian-Bao Han[SUP] 3 [/SUP], Dandan Yu[SUP] 4 [/SUP], Qing-Cui Zou[SUP] 3 [/SUP], Qianjin Liu[SUP] 2 [/SUP], Xiaohong Li[SUP] 2 [/SUP], Guanqin Ma[SUP] 2 [/SUP], Ming-Hua Li[SUP] 5 [/SUP], Yong-Gang Yao[SUP] 6 [/SUP]
Affiliations
Abstract
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[SUP]-/-[/SUP] 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.).
Keywords: MCC950; SARS-CoV-2, NLRP3 inflammasome, Immune overactivation, Cytokine storm.
. 2021 Dec 31;75:103803.
doi: 10.1016/j.ebiom.2021.103803. Online ahead of print.
Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
Jianxiong Zeng[SUP] 1 [/SUP], Xiaochun Xie[SUP] 2 [/SUP], Xiao-Li Feng[SUP] 3 [/SUP], Ling Xu[SUP] 4 [/SUP], Jian-Bao Han[SUP] 3 [/SUP], Dandan Yu[SUP] 4 [/SUP], Qing-Cui Zou[SUP] 3 [/SUP], Qianjin Liu[SUP] 2 [/SUP], Xiaohong Li[SUP] 2 [/SUP], Guanqin Ma[SUP] 2 [/SUP], Ming-Hua Li[SUP] 5 [/SUP], Yong-Gang Yao[SUP] 6 [/SUP]
Affiliations
- PMID: 34979342
- DOI: 10.1016/j.ebiom.2021.103803
Abstract
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[SUP]-/-[/SUP] 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.).
Keywords: MCC950; SARS-CoV-2, NLRP3 inflammasome, Immune overactivation, Cytokine storm.
