Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

Abstract

AimsExtensive evidence suggests inflammatory components participate in the pathogenic processes of acute coronary syndromes (ACS). In this study, we aimed to elucidate the role and mechanism underlying the imbalance of Th17 and Treg cell peripheral populations in the pathogenesis of ACS.Methods and ResultsUsing a flow cytometric analysis, we observed a significantly increased frequency of Th17 cells and a concurrently decreased CD4+CD25+Foxp3+ Treg cells in patients with ACS. To elucidate the mechanism of Th17/Treg imbalance in ACS, 22 inflammatory cytokines were measured using multiplexed immunobead-based assays. Of six elevated cytokines in ACS patients, only IL-6 was positively correlated with a higher Th17 cell level (r = 0.39, P<0.01). Relying on IL-6 stimulating and neutralizing studies, we demonstrated a direct role for IL-6 in sera from ACS patients with an increased frequency of Th17 cells. IL-6 induces the differentiation of Th17 cells from naïve CD4+ T cells through STAT3 activation and RORγt induction. However, we observed that high levels of TGF-β1 inhibited IL-6-dependent Th17 cell differentiation, indicating a complex interplay between the two cytokines in the control of Th17 and Treg cell populations.ConclusionsOur results demonstrate the role of IL-6-STAT3 signaling in ACS through increased Th17 cell differentiation. These findings indicate that IL-6 neutralizing strategies could present novel therapeutic avenues in the treatment of ACS.

HMGB1Modulates the Treg/Th17 Ratio in Atherosclerotic Patients

“…Consistently, Th17-cellrelated cytokine, such as IL-17, increased in AS patients, whereas Tregcellrelated cytokines, such as IL-10 and TGF-, decreased in AS patients. The results we observed in this study were consistent with those of many other studies 13,27,28) . It was suggested that Treg cells and Th17 cells play a vital role in the development of atherosclerosis, and the balance between Treg cells and Th17 cells was disturbed in patients AS patients.…”

Understanding STAT3 signaling in cardiac ischemia

“…STAT proteins range from 750 to 850 amino acids, and display similar structural arrangement of their functional motifs, sharing 20-50 % of their pairwise sequence identity [65]. There are six functional domains, the N-domain/ STAT protein interaction domain, coiled-coil domain (CCD), DNA-binding domain (DBD), linker domain, SH2 domain and the transcriptional activation domain (TAD) [101].…”

Cholesterol and Hematopoietic Stem Cells: Inflammatory Mediators of Atherosclerosis

“…Although a mechanistic connection between cholesterol levels and IL‐17 remains to be determined, IL‐17–producing T H 17 cells and counter‐regulatory T reg cells appear to become imbalanced in acute coronary syndromes. A recent study by Ma et al identified a significant increase in the numbers of IL‐17‐producing T H 17 cells with corresponding reductions in T reg cell types through an increase in IL‐6 levels in patients with acute coronary syndromes [27]. As noted in the studies described above, HSPCs are mobilized in animal models of myocardial infarction and contribute to the progression of atherosclerosis after a heart attack.…”