{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T04:24:49Z","timestamp":1793852689418,"version":"4.6.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,11,28]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Clonal 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 of\n                      <jats:italic>Tet2<\/jats:italic>\n                      CH, whereas inhibition of the inflammasome product interleukin-1\u03b2 appeared to particularly benefit patients with\n                      <jats:italic>TET2<\/jats:italic>\n                      CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]).\n                      <jats:italic>TET2<\/jats:italic>\n                      is 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used cholesterol-loaded TET2-deficient murine and embryonic stem cell\u2013derived isogenic human macrophages to evaluate mechanisms of NLRP3 inflammasome activation in vitro and hypercholesterolemic\n                      <jats:italic>Ldlr<\/jats:italic>\n                      <jats:sup>\n                        \u2212\n                        <jats:italic>\/<\/jats:italic>\n                        \u2212\n                      <\/jats:sup>\n                      mice modeling\n                      <jats:italic>TET2<\/jats:italic>\n                      CH to assess the role of NLRP3 inflammasome activation in atherosclerosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Tet2<\/jats:italic>\n                      deficiency 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 phosphatase\n                      <jats:italic>Dusp10<\/jats:italic>\n                      . Active Tet1-deadCas9\u2013targeted editing of\n                      <jats:italic>Dusp10<\/jats:italic>\n                      promoter methylation abolished cholesterol-induced inflammasome activation in\n                      <jats:italic>Tet2<\/jats:italic>\n                      -deficient macrophages. Increased JNK1 signaling led to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3 (\n                      <jats:italic>BRCA1\/BRCA2<\/jats:italic>\n                      -containing complex subunit 3). Accelerated atherosclerosis and neutrophil extracellular trap formation (NETosis) in\n                      <jats:italic>Tet2<\/jats:italic>\n                      CH 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. Human\n                      <jats:italic>TET2<\/jats:italic>\n                      <jats:sup>\n                        \u2212\n                        <jats:italic>\/<\/jats:italic>\n                        \u2212\n                      <\/jats:sup>\n                      macrophages displayed increased JNK1 and NLRP3 inflammasome activation, especially after cholesterol loading, with reversal by holomycin treatment, indicating human relevance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Hypercholesterolemia 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 in\n                      <jats:italic>TET2<\/jats:italic>\n                      CH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.123.065344","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T05:00:21Z","timestamp":1696222821000},"page":"1764-1777","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":106,"title":["BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in\n                    <i>Tet2<\/i>\n                    Clonal Hematopoiesis"],"prefix":"10.1161","volume":"148","author":[{"given":"Mustafa","family":"Yalcinkaya","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY (M.Y., W.L., T.X., S.A., M.W., N.W., I.T., 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Medicine, Columbia University Irving Medical Center, New York, NY (M.Y., W.L., T.X., S.A., M.W., N.W., I.T., A.R.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Abramowicz","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY (M.Y., W.L., T.X., S.A., M.W., N.W., I.T., A.R.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7002-417X","authenticated-orcid":true,"given":"Eirini P.","family":"Papapetrou","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences (L.-A.T., M.O., E.P.P.), Icahn School of Medicine at Mount Sinai, New York, NY."},{"name":"Tisch Cancer Institute (L.-A.T., M.O., E.P.P.), Icahn School of Medicine at Mount Sinai, New York, NY."},{"name":"Black Family Stem Cell Institute (L.-A.T., M.O., E.P.P.), Icahn School of Medicine at Mount Sinai, New York, 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