Interruption of the OX40–OX40 Ligand Pathway in LDL Receptor–Deficient Mice Causes Regression of Atherosclerosis

Abstract

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.

Mast Cells as Effectors in Atherosclerosis

“…In experimental atherosclerosis, IgE was shown to promote plaque expansion, as mice deficient in the Fcε receptor developed smaller atherosclerotic plaques 63 , but no definitive relation between with mast cell activation and atherosclerosis was established in this study. In another study, interference in the OX40-OX40L signaling pathway was seen to induce regression of atherosclerosis, which was at least partly explained by reduced plasma IgE levels and a concomitant reduction in mast cell numbers and activation status 64 . In contrast to above studies in human populations, plasma IgE levels and low density lipoprotein oxidation failed to correlate in an Asian patient cohort 65 , and furthermore, in line with this observation, plasma total IgE levels did not show any correlation with disease progression or mast cell numbers in a Western population 66 .…”

I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis

“…The role of IL-4 in atherosclerosis remains more controversial. Some studies have indirectly implicated IL-4 as pro-atherosclerotic [15,16], although others found little or no effect on disease in Apoe −/− ; Il-4 −/− mice reconstituted with Il-4 −/− bone marrow [17]. …”

GITR promoter polymorphism contributes to risk of coal workers’ pneumoconiosis: A case–control study from China

“…TNFRSF4 encodes OX40 (CD134), also an important T-cell co-stimulatory molecule. Signaling through OX40 modulates immune response through a variety of proposed mechanisms including reduce the suppressor function of T reg [39,40], and promote conventional T cell responses [41,42]. In previous studies, OX40 signaling was reported to promote the development of rheumatoid arthritis by enhancing expression of Th2 cytokines in the synovial fluid [43,44].…”