Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression

Abstract

Rationale: Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known. Objective: We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling and plaque contraction during atherosclerosis regression. Methods and Results: Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single cell RNA-sequencing of plaque immune cells from revealed that Tregs from regressing plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B anti-sense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution including dampening of the Th1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized pro-resolving lipid mediators. Conclusions: Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

“…The relevance of macrophage egress for plaque regression is controversially debated with several papers arguing against egress [28,29,42,67] and a number of papers that argue for egress [16,30,55]. The discrepancies may arise from differences in the models used to induce normolipidemia and timing related to bead transfer.…”

“…We observed no difference between the groups in either test. Potential macrophage egress was determined using fluorescent bead labeling, as previously described [16,29,55,67]. Fluorescent beads were injected early during atherogenesis after 4 weeks of HCD feeding (Supplemental Fig.6d).…”

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

“…Once activated, T reg cells release antiatherogenic cytokines, including IL-13 and TGF β , to promote plaque stabilization [ 51 ]. In addition, T reg cells can remodel plaques by increasing the number of M2 macrophages, reconstructing damaged fibrous caps, and inhibiting the proliferation of proatherogenic T cells [ 52 ]. The preference of T reg cell differentiation is enhanced in early hypercholesterolemia [ 53 ].…”

Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis

“…Furthermore, immune mediators such as pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), anti-inflammatory cytokines (IL-10), and lipid mediators such as prostaglandins and pro-resolvins also contribute. Pro-inflammatory macrophage responses, Th1 and Th17 T cell responses, and the cytokines and prostaglandins those cells produce promote atherosclerotic progression ( Figure 2 ) [ 15 , 16 ]. By contrast, pro-resolvins, macrophage efferocytosis, anti-phospholipid B cell responses, and T regulatory cell (Treg) responses promote atherosclerosis regression ( Figure 2 ).…”