IL-33 reduces the development of atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1-like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE(-/-) mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33-treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNgamma in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG(1), but decreased IgG(2a), which is consistent with a Th1-to-Th2 switch. IL-33-treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE(-/-) mice compared with control IgG-treated mice. Furthermore, coadministration of an anti-IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.
Miller
Ashley M
AM
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, Scotland, UK.
Xu
Damo
D
Asquith
Darren L
DL
Denby
Laura
L
Li
Yubin
Y
Sattar
Naveed
N
Baker
Andrew H
AH
McInnes
Iain B
IB
Liew
Foo Y
FY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000276:immunology* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004036:Diet, Atherogenic; D042783:Endothelial Cells; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D007136:Immunoglobulins; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; C099252:oxidized low density lipoprotein