BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.
BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.
复制标题
BRCC3 介导的 NLRP3 去泛素化促进 Tet2 克隆造血过程中炎症小体激活和动脉粥样硬化。
DOI：
10.1161/circulationaha.123.065344
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发表时间：
2023
期刊：
影响因子：
37.8
通讯作者：
Tall,AlanR
中科院分区：
文献类型：
--
作者：
Yalcinkaya,Mustafa;Liu,Wenli;Thomas,Leigh-Anne;Olszewska,Malgorzata;Xiao,Tong;Abramowicz,Sandra;Papapetrou,EiriniP;Westerterp,Marit;Wang,Nan;Tabas,Ira;Tall,AlanR
BACKGROUNDClonal hematopoiesis (CH) has emerged as an independent risk factor for atherosclerotic cardiovascular disease, with activation of macrophage inflammasomes as a potential underlying mechanism. The NLRP3 (NLR family pyrin domain containing 3) inflammasome has a key role in promoting atherosclerosis in mouse models ofTet2CH, whereas inhibition of the inflammasome product interleukin-1β appeared to particularly benefit patients withTET2CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]).TET2is an epigenetic modifier that decreases promoter methylation. However, the mechanisms underlying macrophage NLRP3 inflammasome activation in TET2 (Tet methylcytosine dioxygenase 2) deficiency and potential links with epigenetic modifications are poorly understood.METHODSWe used cholesterol-loaded TET2-deficient murine and embryonic stem cell–derived isogenic human macrophages to evaluate mechanisms of NLRP3 inflammasome activation in vitro and hypercholesterolemicLdlr−/−mice modelingTET2CH to assess the role of NLRP3 inflammasome activation in atherosclerosis.RESULTSTet2deficiency in murine macrophages acted synergistically with cholesterol loading in cell culture and with hypercholesterolemia in vivo to increase JNK1 (c-Jun N-terminal kinase 1) phosphorylation and NLRP3 inflammasome activation. The mechanism of JNK (c-Jun N-terminal kinase) activation in TET2 deficiency was increased promoter methylation and decreased expression of the JNK-inactivating dual-specificity phosphataseDusp10. Active Tet1-deadCas9–targeted editing ofDusp10promoter methylation abolished cholesterol-induced inflammasome activation inTet2-deficient macrophages. Increased JNK1 signaling led to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3 (BRCA1/BRCA2-containing complex subunit 3). Accelerated atherosclerosis and neutrophil extracellular trap formation (NETosis) inTet2CH mice were reversed by holomycin, a BRCC3 deubiquitinase inhibitor, and also by hematopoietic deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex. HumanTET2−/−macrophages displayed increased JNK1 and NLRP3 inflammasome activation, especially after cholesterol loading, with reversal by holomycin treatment, indicating human relevance.CONCLUSIONSHypercholesterolemia and TET2 deficiency converge on a common pathway of NLRP3 inflammasome activation mediated by JNK1 activation and BRCC3-mediated NLRP3 deubiquitylation, with potential therapeutic implications for the prevention of cardiovascular disease inTET2CH.
