{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:15:52Z","timestamp":1790082952361,"version":"4.0.1"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1\u03b2 (interleukin-1\u03b2); this significantly reduced cardiovascular events. However, whether IL-1\u03b2 regulates early disease, particularly LDL transcytosis, remains unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1\u03b2. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1\u03b2 and LDL to visualize acute LDL deposition in the aortic arch.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Exposure to picomolar concentrations of IL-1\u03b2 induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1\u03b2 increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1\u03b2 on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1\u03b2, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1\u03b2. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1\u03b2 increased LDL transcytosis in the aortic arch of wild-type but not\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1\u03b2\u2013induced LDL accumulation in the aorta.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>IL-1\u03b2 induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1\u03b2 may contribute to the acceleration of early disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.124.320940","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T05:01:02Z","timestamp":1720674062000},"page":"2053-2068","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["IL-1\u03b2 Induces LDL Transcytosis by a Novel Pathway Involving LDLR and Rab27a"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2650-5037","authenticated-orcid":true,"given":"Erika","family":"Jang","sequence":"first","affiliation":[{"name":"Keenan Centre for Biomedical Research, St. Michael\u2019s Hospital, Toronto, ON, Canada (E.J., T.W.W.H., C.W., W.L.L.)."},{"name":"Department of Laboratory Medicine and Pathobiology (E.J., T.W.W.H., W.L.L.), University of Toronto, ON, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-7859","authenticated-orcid":true,"given":"Tse Wing Winnie","family":"Ho","sequence":"additional","affiliation":[{"name":"Keenan Centre for Biomedical Research, St. Michael\u2019s Hospital, Toronto, ON, Canada (E.J., T.W.W.H., C.W., W.L.L.)."},{"name":"Department of Laboratory Medicine and Pathobiology (E.J., T.W.W.H., W.L.L.), University of Toronto, ON, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-7789","authenticated-orcid":true,"given":"John H.","family":"Brumell","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada (J.H.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada (F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsen","family":"Wang","sequence":"additional","affiliation":[{"name":"Keenan Centre for Biomedical Research, St. Michael\u2019s Hospital, Toronto, ON, Canada (E.J., T.W.W.H., C.W., W.L.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1788-6587","authenticated-orcid":true,"given":"Warren L.","family":"Lee","sequence":"additional","affiliation":[{"name":"Keenan Centre for Biomedical Research, St. Michael\u2019s Hospital, Toronto, ON, Canada (E.J., T.W.W.H., C.W., W.L.L.)."},{"name":"Department of Laboratory Medicine and Pathobiology (E.J., T.W.W.H., W.L.L.), University of Toronto, ON, Canada."},{"name":"Department of Biochemistry (W.L.L.), University of Toronto, ON, Canada."},{"name":"Department of Medicine and the Interdepartmental Division of Critical Care Medicine (W.L.L.), University of Toronto, ON, 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