{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:07:49Z","timestamp":1791472069720,"version":"4.3.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,8,28]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)\u20131\u03b2 reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1\u03b2 secretion increase cardiovascular risk. IL-1\u03b2 and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1\/G1) mediate cholesterol efflux to high-density lipoprotein, and\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              deficiency in myeloid cells leads to cholesterol accumulation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              deficiency and concomitant deficiency of the inflammasome components\n              <jats:italic>Nlrp3<\/jats:italic>\n              or\n              <jats:italic>Caspase-1\/11<\/jats:italic>\n              . Bone marrow from these mice was transplanted into\n              <jats:italic>Ldlr<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              recipients, which were fed a Western-type diet.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Myeloid\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              deficiency increased plasma IL-18 levels in\n              <jats:italic>Ldlr<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice and induced IL-1\u03b2 and IL-18 secretion in splenocytes, which was reversed by\n              <jats:italic>Nlrp3<\/jats:italic>\n              or\n              <jats:italic>Caspase-1\/11<\/jats:italic>\n              deficiency, indicating activation of the NLRP3 inflammasome.\n              <jats:italic>Nlrp3<\/jats:italic>\n              or\n              <jats:italic>Caspase-1\/11<\/jats:italic>\n              deficiency decreased atherosclerotic lesion size in myeloid\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              -deficient\n              <jats:italic>Ldlr<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice. Myeloid\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by\n              <jats:italic>Nlrp3<\/jats:italic>\n              or\n              <jats:italic>Caspase-1\/11<\/jats:italic>\n              deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid\n              <jats:italic>Abca1\/g1<\/jats:italic>\n              deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in\n              <jats:italic>ABCA1<\/jats:italic>\n              and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1\u03b2 and IL-18 levels.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.117.032636","type":"journal-article","created":{"date-parts":[[2018,3,27]],"date-time":"2018-03-27T09:25:14Z","timestamp":1522142714000},"page":"898-912","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":329,"title":["Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis"],"prefix":"10.1161","volume":"138","author":[{"given":"Marit","family":"Westerterp","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"},{"name":"Department of Pediatrics, Section of Molecular Genetics (M.W.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Fotakis","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireille","family":"Ouimet","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, New York University Medical Center, NY (M.O., K.J.M.)"},{"name":"University of Ottawa Heart Institute, and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada (M.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea E.","family":"Bochem","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"},{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands (A.E.B., E.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiology (H.Z., M.P.R.), Department of Medicine, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Molusky","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Abramowicz","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"la Bastide-van Gemert","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (S.l.B-v.G.), University of Groningen, University Medical Center Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie L.","family":"Welch","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muredach P.","family":"Reilly","sequence":"additional","affiliation":[{"name":"Division of Cardiology (H.Z., M.P.R.), Department of Medicine, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik S.","family":"Stroes","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands (A.E.B., E.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn J.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, New York University Medical Center, NY (M.O., K.J.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Tall","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., 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