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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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Detalles Bibliográficos
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
Descripción
Sumario: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.