Modulation of Peripheral CD4+CD25+Foxp3+ Regulatory T Cells Ameliorates Surgical Stress-Induced Atherosclerotic Plaque Progression in ApoE-Deficient Mice

Abstract

Systemic inflammation associated with major surgery rapidly accelerates atherosclerotic plaque progression in mice. Regulatory T cells (Tregs) have emerged as important modulators of atherogenesis. In coronary artery disease patients, low frequency of Tregs constitutes an independent risk factor for cardiovascular complications after non-cardiac surgery. In this exploratory analysis, we investigate whether preoperative Treg levels affect surgery-induced atherosclerotic lesion destabilization in a murine model of perioperative stress. After 9 weeks of high-cholesterol diet, atherosclerotic apolipoprotein E-deficient mice with modulated Treg levels were subjected to a 30-minute surgical procedure consisting of general isoflurane anesthesia, laparotomy and moderate blood loss. Controls underwent general anesthesia only. Brachiocephalic arteries were harvested 3 days after the intervention for histomorphological analyses of atherosclerotic plaques. Tregs were depleted by a single dose of anti-CD25 monoclonal antibody (mAb) administered 6 days prior to the intervention. Expansion of Tregs was induced by daily injections of IL-2/anti-IL-2 complex (IL-2C) on three consecutive days starting 3 days before surgery. Isotype-matched antibodies and PBS served as controls. Antibody-mediated modulation was Treg-specific. IL-2C treatment resulted in an eight-fold elevation of peripheral CD4+CD25+Foxp3+ Tregs compared to mice administered with anti-CD25 mAb. In mice treated with PBS and anti-CD25 mAb, surgical stress response caused a significant increase of atherosclerotic plaque necrosis (PBS: p < 0.001; anti-CD25 mAb: p = 0.037). Preoperative Treg expansion abrogated perioperative necrotic core formation (p = 0.556) and significantly enhanced postoperative atherosclerotic plaque stability compared to PBS-treated mice (p = 0.036). Postoperative plaque volume (p = 0.960), stenosis (p = 0.693), lesional collagen (p = 0.258), as well as the relative macrophage (p = 0.625) and smooth muscle cell content (p = 0.178) remained largely unaffected by preoperative Treg levels. In atherosclerotic mice, therapeutic expansion of Tregs prior to major surgery mitigates rapid effects on perioperative stress-driven atherosclerotic plaque destabilization. Future studies will show, whether short-term interventions modulating perioperative inflammation qualify for prevention of cardiovascular events associated with major non-cardiac surgery.

Pilot study of the FoxP3+ T lymphocyte count and its relationship with the Gensini score in patients with coronary heart disease and type 2 diabetes mellitus from a South American cohort

“…The level of insulin resistance may have a direct impact on CCL22 production, given the relationship we found between LPS-stimulated CCL22 production by mononuclear leukocytes and the TG/glucose ratio in patients. A low frequency of Treg cells was shown to be associated with the destabilization of atherosclerotic plaques in experimental animals [15]. It can be assumed that in T2DM there is a CCL22- mediated alteration in the recruitment of Treg lymphocytes to the atheroma, which ultimately contributes to Treg deficiency in the vascular wall, increased inflammation and the progression of atherosclerosis.…”

T-lymphocytes FoxP3+ and their interconnection with the severity of coronary atherosclerosis in patients with coronary artery disease and diabetes mellitus type 2: a pilot study

“…ОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕ CCL22 мононуклеарными лейкоцитами и индексом ТГ/ глюкоза у пациентов. Показано, что низкая частота Treg-лимфоцитов ассоциировалась с дестабилизацией атеросклеротических бляшек у экспериментальных животных [15]. Можно предположить, что при СД2 наблюдается CCL22-опосредованное нарушение привлечения Treg-лимфоцитов в атерому, что в конце концов способствует дефициту Treg в стенке сосуда, увеличению воспаления и прогрессированию атеросклероза [6].…”

Regulatory T cells and cardiovascular diseases

“…Anti-CD25 antibodies, which deplete Tregs, increased lesion area and plaque vulnerability in apolipoprotein-E-deficient ( ApoE –/– ) mice. [ 39 ] Diphtheria toxin-mediated Treg depletion led to more severe AS lesions in Low density lipoprotein receptor deficient ( LDLR –/– ) mice. [ 40 ] Conversely, transferring Tregs to ApoE –/– mice led to AS regression and enhanced plaque stability.…”