Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30291237.
- Also identified by DOI 10.1038/s41467-018-06522-5 and PMC identifier 6173702.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sub>mCas9/gNLRP3</sub>), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLAN<sub>mCas9/gNLRP3</sub> mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLAN<sub>mCas9/gNLRP3</sub> 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.
Medical subject headings
- Gene Editing
- Genetic Therapy
- Inflammasomes
- Inflammation
- NLR Family, Pyrin Domain-Containing 3 Protein