Interruption of the OX40-OX40 ligand pathway in LDL receptor-deficient mice causes regression of atherosclerosis.
Patients suffering from cardiovascular disease have well-established atherosclerotic lesions, rendering lesion regression of therapeutic interest. The OX40 (TNFRSF4)-OX40 ligand (OX40L; TNFSF4) pathway is important for the proliferation and survival of T cells, stimulates B cells, and is associated with cardiovascular disease. We hypothesized that interference with the OX40-OX40L pathway, in combination with decreases in cholesterol, may induce regression of atherosclerosis. LDLr(-/-) mice were fed a Western-type diet for 10 wk, after which they received chow diet and were treated with anti-OX40L or PBS for 10 wk. A significant regression of lesions was observed in the aorta and aortic arch of anti-OX40L-treated mice compared with control mice. Interference of the OX40-OX40L pathway reduced Th2 responses, as shown by decreases in GATA-3 and IL-4 levels. Also, IgE levels were decreased, as demonstrated by reduced mast cell presence and activation. Notably, IL-5 production by T and B1 cells was increased, thus enhancing atheroprotective oxidized low-density lipoprotein-specific IgM production. The increase in IL-5 production and IgM was mediated by IL-33 production by APCs upon OX40L blockade. We conclude that interruption of the OX40-OX40L signaling pathway, combined with decreases in dietary cholesterol, induces the regression of atherosclerosis through induction of IL-5-producing T cells and oxidized low-density lipoprotein-specific IgM and reductions in Th2 and mast cells.
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2300 RA, The Netherlands;
Amanda C
AC
Foks
Gijs H M
GH
van Puijvelde
Ilze
I
Bot
Mariette N D
MN
ter Borg
Kim L L
KL
Habets
Jason L
JL
Johnson
Hideo
H
Yagita
Theo J C
TJ
van Berkel
Johan
J
Kuiper
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D007075:Immunoglobulin M / Q000276:immunology; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053278:OX40 Ligand; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D053262:Receptors, OX40 / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C506535:Il33 protein, mouse; D007075:Immunoglobulin M; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D011973:Receptors, LDL; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D015847:Interleukin-4; D007073:Immunoglobulin E; D002784:Cholesterol