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CCR5-Mediated Reprogramming of Regulatory T Cells and Monocytic-Myeloid-Derived Suppressor Cells in Young
Komal Sagar1, Shamima Akhtar1, Nikita Kumar1
1Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India.
Abstract:
Chemokine receptor CCR5 is upregulated in the regulatory T cells (Tregs) and monocytic-myeloid-derived suppressor cells (M-MDSCs) of young dyslipidemic individuals. In this study, we investigated the role of CCR5 in regulating the phenotypic and functional plasticity of Tregs and M-MDSCs during the preclinical phase of atherosclerosis. Inflammatory conditions induce a phenotypic shift in Tregs and M-MDSCs, characterised by enhanced expression of CCR5 and pro-inflammatory cytokines. Tregs from dyslipidemic (DLP) and coronary artery disease (CAD) patients exhibited a mixed Th1/Th17/Treg phenotype, whilst M-MDSCs displayed elevated markers of activation and inflammation. CCR5 inhibition via DAPTA (10-8 M) restored the immune suppressive phenotype and function of Tregs and M-MDSCs in vitro. Migration of dysfunctional Tregs and M-MDSCs to CCL5 stimulus was also reduced after DAPTA treatment in vitro. In vivo, DAPTA reduced IL-12 expression and elevated IL-10 expression in Tregs and M-MDSCs. Therapeutically targeting CCR5 in Tregs and M-MDSCs of young naive dyslipidemic individuals aids in the dampening of early inflammation and can prevent the progression of atherosclerosis.
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