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Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases

The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optim...

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Autores principales: Xu, Congfei, Lu, Zidong, Luo, Yingli, Liu, Yang, Cao, Zhiting, Shen, Song, Li, Hongjun, Liu, Jing, Chen, Kaige, Chen, Zhiyao, Yang, Xianzhu, Gu, Zhen, Wang, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173702/
https://www.ncbi.nlm.nih.gov/pubmed/30291237
http://dx.doi.org/10.1038/s41467-018-06522-5
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author Xu, Congfei
Lu, Zidong
Luo, Yingli
Liu, Yang
Cao, Zhiting
Shen, Song
Li, Hongjun
Liu, Jing
Chen, Kaige
Chen, Zhiyao
Yang, Xianzhu
Gu, Zhen
Wang, Jun
author_facet Xu, Congfei
Lu, Zidong
Luo, Yingli
Liu, Yang
Cao, Zhiting
Shen, Song
Li, Hongjun
Liu, Jing
Chen, Kaige
Chen, Zhiyao
Yang, Xianzhu
Gu, Zhen
Wang, Jun
author_sort Xu, Congfei
collection PubMed
description The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLAN(mCas9/gNLRP3)), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLAN(mCas9/gNLRP3) mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLAN(mCas9/gNLRP3) treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages.
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spelling pubmed-61737022018-10-09 Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases Xu, Congfei Lu, Zidong Luo, Yingli Liu, Yang Cao, Zhiting Shen, Song Li, Hongjun Liu, Jing Chen, Kaige Chen, Zhiyao Yang, Xianzhu Gu, Zhen Wang, Jun Nat Commun Article The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLAN(mCas9/gNLRP3)), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLAN(mCas9/gNLRP3) mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLAN(mCas9/gNLRP3) treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages. Nature Publishing Group UK 2018-10-05 /pmc/articles/PMC6173702/ /pubmed/30291237 http://dx.doi.org/10.1038/s41467-018-06522-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xu, Congfei
Lu, Zidong
Luo, Yingli
Liu, Yang
Cao, Zhiting
Shen, Song
Li, Hongjun
Liu, Jing
Chen, Kaige
Chen, Zhiyao
Yang, Xianzhu
Gu, Zhen
Wang, Jun
Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title_full Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title_fullStr Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title_full_unstemmed Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title_short Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
title_sort targeting of nlrp3 inflammasome with gene editing for the amelioration of inflammatory diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173702/
https://www.ncbi.nlm.nih.gov/pubmed/30291237
http://dx.doi.org/10.1038/s41467-018-06522-5
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