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Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages

Background and aims: Macrophages play a critical role in the development of liver diseases. As an NAD(+)-dependent histone deacetylase, SIRT1 inhibits liver inflammation and fibrosis, but the mechanisms are not fully understood. Our aim was to investigate the molecular mechanism of SIRT1 in macropha...

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Autores principales: He, Shuli, Wang, Yaru, Liu, Jinying, Li, Pengju, Luo, Xiaoying, Zhang, Bingyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087625/
https://www.ncbi.nlm.nih.gov/pubmed/37057212
http://dx.doi.org/10.7150/ijms.77955
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author He, Shuli
Wang, Yaru
Liu, Jinying
Li, Pengju
Luo, Xiaoying
Zhang, Bingyong
author_facet He, Shuli
Wang, Yaru
Liu, Jinying
Li, Pengju
Luo, Xiaoying
Zhang, Bingyong
author_sort He, Shuli
collection PubMed
description Background and aims: Macrophages play a critical role in the development of liver diseases. As an NAD(+)-dependent histone deacetylase, SIRT1 inhibits liver inflammation and fibrosis, but the mechanisms are not fully understood. Our aim was to investigate the molecular mechanism of SIRT1 in macrophages in liver inflammation and fibrosis. Methods: We employed the CCl4-induced hepatic fibrosis rat models and cultured murine macrophages RAW 264.7 in vitro to explore the anti-fibrosis effect of SIRT1. The content of cytokines was measured with ELISA. The expression of proteins associated with the NF-κB /NLPR3 signaling pathway was detected by Western blot, co-immunoprecipitation, and immunofluorescence. SIRT1, NF-κB, and NLRP3 genes were knocked down in RAW 264.7 cells by small interfering RNA (siRNA) transfection. Results: The expression of NF-κB p65, NLRP3, α-SMA, and iNOS increased in liver tissue, with high plasma LPS level and low expression of SIRT1 in CCl4-induced rat models. Overexpressing SIRT1 could inhibit these protein levels, decrease plasma LPS level, and attenuate liver injury and fibrosis. In vitro, LPS induced cytomorphology changes and up-regulated NF-κB/NLRP3 pathway, with the low expression of SIRT1 in RAW 264.7; meanwhile, the secretion of inflammatory factors increased. Nevertheless, knockdown of NF-κB or NLRP3 and activation of SIRT1 inhibited inflammation of macrophages; inhibition or knockdown of SIRT1 enhanced macrophage inflammation. Furthermore, activation of SIRT1 could inhibit LPS-treated macrophages from activating hepatic stellate cells (HSCs). Conclusions: Activating SIRT1 inhibits the inflammation in macrophages by down-regulating NLRP3 pathway through deacetylating NF-κB p65, which in turn inhibits the activation of HSCs to alleviate hepatic inflammation and fibrosis.
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spelling pubmed-100876252023-04-12 Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages He, Shuli Wang, Yaru Liu, Jinying Li, Pengju Luo, Xiaoying Zhang, Bingyong Int J Med Sci Research Paper Background and aims: Macrophages play a critical role in the development of liver diseases. As an NAD(+)-dependent histone deacetylase, SIRT1 inhibits liver inflammation and fibrosis, but the mechanisms are not fully understood. Our aim was to investigate the molecular mechanism of SIRT1 in macrophages in liver inflammation and fibrosis. Methods: We employed the CCl4-induced hepatic fibrosis rat models and cultured murine macrophages RAW 264.7 in vitro to explore the anti-fibrosis effect of SIRT1. The content of cytokines was measured with ELISA. The expression of proteins associated with the NF-κB /NLPR3 signaling pathway was detected by Western blot, co-immunoprecipitation, and immunofluorescence. SIRT1, NF-κB, and NLRP3 genes were knocked down in RAW 264.7 cells by small interfering RNA (siRNA) transfection. Results: The expression of NF-κB p65, NLRP3, α-SMA, and iNOS increased in liver tissue, with high plasma LPS level and low expression of SIRT1 in CCl4-induced rat models. Overexpressing SIRT1 could inhibit these protein levels, decrease plasma LPS level, and attenuate liver injury and fibrosis. In vitro, LPS induced cytomorphology changes and up-regulated NF-κB/NLRP3 pathway, with the low expression of SIRT1 in RAW 264.7; meanwhile, the secretion of inflammatory factors increased. Nevertheless, knockdown of NF-κB or NLRP3 and activation of SIRT1 inhibited inflammation of macrophages; inhibition or knockdown of SIRT1 enhanced macrophage inflammation. Furthermore, activation of SIRT1 could inhibit LPS-treated macrophages from activating hepatic stellate cells (HSCs). Conclusions: Activating SIRT1 inhibits the inflammation in macrophages by down-regulating NLRP3 pathway through deacetylating NF-κB p65, which in turn inhibits the activation of HSCs to alleviate hepatic inflammation and fibrosis. Ivyspring International Publisher 2023-02-21 /pmc/articles/PMC10087625/ /pubmed/37057212 http://dx.doi.org/10.7150/ijms.77955 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
He, Shuli
Wang, Yaru
Liu, Jinying
Li, Pengju
Luo, Xiaoying
Zhang, Bingyong
Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title_full Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title_fullStr Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title_full_unstemmed Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title_short Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages
title_sort activating sirt1 deacetylates nf-κb p65 to alleviate liver inflammation and fibrosis via inhibiting nlrp3 pathway in macrophages
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087625/
https://www.ncbi.nlm.nih.gov/pubmed/37057212
http://dx.doi.org/10.7150/ijms.77955
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