Atheroprotective immunity and interleukin-10 linked to reduced plaque stability and recurrent cardiovascular events
Atherosclerotic cardiovascular disease remains a major cause of death worldwide. Autoimmunity to low-density lipoprotein (LDL) has been implicated in the disease process and immunization with LDL components proposed as a preventive strategy. However, mechanisms of atheroprotective immunity remain insufficiently characterized. Two different T cell receptor transgenic mouse strains with T cells reactive against the LDL protein, apoB100 (BT1 and BT3) were crossbred with human APOB100-transgenic Ldlr-/- (HuBL) mice, and atherosclerosis was evaluated. In 52-week-old BT1xHuBL mice, a lower atherosclerotic burden was observed in the aorta, mirrored by reduced plasma cholesterol and elevated anti-apoB100 antibodies. BT3xHuBL mice also exhibited a decrease in aortic atherosclerosis; however, no reduction in plasma cholesterol levels was noted. Instead, type 1 regulatory T cell responses with interleukin (IL)-10 production were mounted. This response was associated with reduced collagen content and a lower stability index of the atherosclerotic lesions. In human carotid artery plaques, IL10 mRNA levels were negatively correlated with collagen expression, and IL-10 was found to inhibit collagen production in vascular smooth muscle cells. We conclude that atheroprotective apoB immunity elicits two distinct pathways: lipid-lowering immune reactions and local anti-inflammatory IL-10 production. Since the latter is associated with decreased plaque stability and cardiovascular events, treatments aimed at increasing IL-10 signaling over extended periods to reduce vascular inflammation need reconsideration. Overall design: RNA-seq profiling of the aorta and liver from HuBL and BT3xHuBL mice after 52 weeks on a normal laboratory diet.