CCR5-Mediated Reprogramming of Regulatory T Cells and Monocytic-Myeloid-Derived Suppressor Cells in Young Dyslipidemic Individuals: A Plausible Therapeutic Approach
Komal Sagar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorShamima Akhtar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorNikita Kumar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorAnil Kumar Tomar
Department of Biophysics, AIIMS, New Delhi, India
Search for more papers by this authorMilind P. Hote
Department of Cardiothoracic and Vascular Surgery, AIIMS, New Delhi, India
Search for more papers by this authorCorresponding Author
Alpana Sharma
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Correspondence:
Alpana Sharma ([email protected])
Search for more papers by this authorKomal Sagar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorShamima Akhtar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorNikita Kumar
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Search for more papers by this authorAnil Kumar Tomar
Department of Biophysics, AIIMS, New Delhi, India
Search for more papers by this authorMilind P. Hote
Department of Cardiothoracic and Vascular Surgery, AIIMS, New Delhi, India
Search for more papers by this authorCorresponding Author
Alpana Sharma
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
Correspondence:
Alpana Sharma ([email protected])
Search for more papers by this authorFunding: This work was supported by the Indian Council of Medical Research (ICMR), India (61/2/2019/BMS/IMM) to Prof. Alpana Sharma and Junior Research Fellowship from the University Grants Commission (UGC-JRF) (191620007160) to Komal Sagar for pursuing a doctoral thesis.
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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Supporting Information
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Data S1. Supporting Information. |
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