Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice

Abstract

Background: The interplay between innate and adaptive immunity is central in life-threatening clinical complications of atherosclerosis such as myocardial infarction and stroke. The specific mechanisms involved and their protective versus detrimental effects in the disease process remain poorly understood. We have previously shown that higher levels of Toll-like receptor 7 (TLR7) expression in human atherosclerotic lesions are correlated with better patient outcome.

Objective: In this study, we explored whether TLR7 activation can ameliorate disease in experimental atherosclerosis in mice.

Methods: Apolipoprotein E deficient mice (Apoe^-/- ) with established disease were injected for five weeks intraperitoneally with the TLR7 ligand R848. Local effects were evaluated by characterization of the lesion. Systemic effects of the treatment were investigated by immune composition analysis in the spleen and plasma measurements.

Results: The in vivo treatment arrested lesion progression in the aorta. We also detected expansion of marginal zone B cells and T_reg in the spleen together with increased plasma IgM antibodies against oxidized low-density lipoprotein (oxLDL) and reduced plasma cholesterol levels. These changes were accompanied by increased accumulation of IgM antibodies, decreased necrosis and fewer apoptotic cells in atherosclerotic lesions.

Conclusions: Our findings show that TLR7 stimulation could ameliorate atherosclerotic lesion burden and reduce plasma cholesterol in Apoe^-/- mice. TLR7 stimulation was associated with an atheroprotective B-cell and T_reg response, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.

Keywords: B lymphocyte; cholesterol; immunoglobulin M; inflammation; oxidized low-density lipoprotein; regulatory T cell.