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Cholesterol trafficking to the ER leads to the activation of CaMKII/JNK/NLRP3 and promotes atherosclerosis.

Authors :
Yalcinkaya M
Liu W
Xiao T
Abramowicz S
Wang R
Wang N
Westerterp M
Tall AR
Source :
Journal of lipid research [J Lipid Res] 2024 Apr; Vol. 65 (4), pp. 100534. Date of Electronic Publication: 2024 Mar 22.
Publication Year :
2024

Abstract

The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr <superscript>-/-</superscript> mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.<br />Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Tall is a member of the SAB of Tensixteen Bio and Beren Therapeutics.<br /> (Published by Elsevier Inc.)

Details

Language :
English
ISSN :
1539-7262
Volume :
65
Issue :
4
Database :
MEDLINE
Journal :
Journal of lipid research
Publication Type :
Academic Journal
Accession number :
38522750
Full Text :
https://doi.org/10.1016/j.jlr.2024.100534