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 Treg 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 Treg response, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

“…The role of TLR7 has previously been investigated in atherosclerosis [19,21]. Plaques from patients operated for carotid stenosis showed infiltration of TLR7+ macrophages and T cells.…”

“…Furthermore, patients with a higher level of TLR7 in the plaque had better outcome [19]. In an experimental atherosclerosis model, treatment with TLR7 ligand could ameliorate atherosclerosis [21]. Although atherosclerosis and aortic valve stenosis share some risk factors and pathophysiological mechanisms they present several differences as well.…”

“…The ligands that have been identified for TLR7 so far are single stranded RNA and imidazoquinoline derivatives [18]. Interestingly, TLR7 has been shown to be protective in atherosclerosis [19][20][21]. In human carotid atherosclerotic lesions TLR7 was correlated with M2 macrophage subtype [20].…”

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“…Some other investigational drugs are already in clinical trials (https://www.fda. gov/consumers/consumer-updates/know-your-treatment-optionscovid- 19).…”

A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: Clinical and therapeutic implications

“…However, the type of specific response initiated by TLR depends on the recruitment of binding adapter proteins containing the Toll-IL-1 receptor domain [28]. Available studies demonstrate varying functions according to the receptor subtype, with some being considered proatherogenic while others could act in a protective way [29][30][31][32].…”