CCR5-mediated homing of regulatory T cells and monocytic-myeloid derived suppressor cells to dysfunctional endothelium contributes to early atherosclerosis

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-09-10 DOI:10.1111/imm.13859
Shamima Akhtar, Komal Sagar, Ambuj Roy, Milind P. Hote, Sudheer Arava, Alpana Sharma
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Abstract

A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.

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CCR5 介导的调节性 T 细胞和单核细胞-骨髓细胞脱髓鞘抑制细胞向功能失调的内皮细胞归巢,导致早期动脉粥样硬化
众所周知,免疫调节细胞和炎症细胞之间的失衡会导致动脉粥样硬化。然而,其确切机制尚不清楚。在这里,我们研究了无症状的冠状动脉疾病(CAD)危险因素暴露的年轻人(血脂异常[DLP]组)和稳定的CAD患者(CAD组)的免疫调节细胞归巢情况,主要是调节性T细胞(Tregs)和髓源抑制细胞(MDSCs)亚群。与健康对照组(HCs)相比,DLP 组和 CAD 组的 Tregs 频率都有所降低,但两组中的 CCR5 表达水平都很高。仅在 CAD 患者中,单核髓源性抑制细胞(M-MDSCs)的数量增加,而多形核髓源性抑制细胞(PMN-MDSCs)的数量减少。有趣的是,DLP 组的 M-MDSCs 虽然在频率上没有变化,但却表达了高水平的 CCR5。DLP 组血清中的趋化因子(CCL5、CX3CL1、CCL26)和炎症细胞因子(IL-6、IL-1β、IFN-γ、TNF-α)水平较高。炎症细胞因子的刺激增强了从 HCs 分离的 Tregs 和 M-MDSCs 中 CCR5 的表达。活化的内皮细胞在体外显示出 CX3CL1 和 CCL5 水平的升高。用 D-Ala 肽 T-酰胺(DAPTA)阻断 CCR5 可增加高脂饮食 C57Bl6 小鼠的 Treg 和 M-MDSC 频率。在加速动脉粥样硬化模型中,DAPTA 处理可导致富含平滑肌的斑块形成,巨噬细胞减少。因此,我们发现在动脉粥样硬化的无症状阶段,CCR5-CCL5 轴有助于招募 Tregs 和 M-MDSCs 到功能失调的内皮,从而促进动脉粥样硬化的进展。针对无症状和暴露于 CAD 危险因素的个体的 CCR5 药物可能是减少动脉粥样硬化发生的一种新型治疗方法。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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