title: IL-33 reduces macrophage foam cell formation.
abstract: The development of atherosclerosis, a chronic inflammatory disease characterized by the formation of arterial fibrotic plaques, has been shown to be reduced by IL-33 in vivo. However, whether IL-33 can directly affect macrophage foam cell formation, a key feature of atherosclerotic plaques, has not been determined. In this study, we investigated whether IL-33 reduces macrophage foam cell accumulation in vivo and if IL-33 reduces their formation in vitro using THP-1 and primary human monocyte-derived macrophages. In Apolipoprotein E(-/-) mice fed on a high fat diet, IL-33 treatment significantly reduced the accumulation of macrophage-derived foam cells in atherosclerotic plaques. IL-33 also reduced macrophage foam cell formation in vitro by decreasing acetylated and oxidized low-density lipoprotein uptake, reducing intracellular total and esterified cholesterol content and enhancing cholesterol efflux. These changes were associated with IL-33-mediated reduction in the expression of genes involved in modified low-density lipoprotein uptake, such as CD36, and simultaneous increase in genes involved in cholesterol efflux, including Apolipoprotein E, thereby providing a mechanism for such an action for this cytokine. IL-33 also decreased the expression of key genes implicated in cholesterol esterification and triglyceride storage, including Acyl-CoA:cholesterol acyltransferase 1 and Adipocyte differentiation-related protein. Furthermore, using bone marrow-derived macrophages from ST2(-/-) mice, we demonstrate that the IL-33 receptor, ST2, is integral to the action of IL-33 on macrophage foam cell formation. In conclusion, IL-33 has a protective role in atherosclerosis by reducing macrophage foam cell formation suggesting that IL-33 maybe a potential therapeutic agent against atherosclerosis.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.forename: Daryn R
authors.initials: DR
authors.lastname: Michael
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Salter
authors.forename: Tim G
authors.initials: TG
authors.lastname: Ashlin
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Calder
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Miller
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Dipak P
authors.initials: DP
authors.lastname: Ramji
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005260:Female; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000493:pharmacokinetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D002788:Cholesterol Esters; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008077:Lipoproteins, LDL; D018123:Receptors, Interleukin; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol