MicroRNAs Targeting Programmed Cell Death Protein 1 (PD-1) Promote Natural Killer Cell Exhaustion in Rheumatoid Arthritis

Maryam Hemmatzadeh; Elham Ahangar Parvin; Alireza Ghanavatinejad; Narges Rostami; Mehrzad Hajaliloo; Navid Shomali; Hamed Mohammadi; Farhad  Jadidi-Niaragh

doi:10.18502/ijaai.v21i6.11524

Maryam Hemmatzadeh Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
Elham Ahangar Parvin Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
Alireza Ghanavatinejad Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran
Narges Rostami Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
Mehrzad Hajaliloo Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Navid Shomali Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
Hamed Mohammadi Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
Farhad Jadidi-Niaragh Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

DOI: https://doi.org/10.18502/ijaai.v21i6.11524

Keywords: MicroRNA; Natural killer cell; NK cell exhaustion; Programmed cell death protein 1; Rheumatoid arthritis

Abstract

Natural killer (NK) cells play a role in the pathogenesis of rheumatoid arthritis (RA). Upregulated levels of programmed cell death protein 1 (PD-1) is a sign of exhausted NK cells that could be regulated by microRNAs (miRNAs). In this investigation, we determined PD‑1 expression on NK cells (as a representation of NK cell exhaustion) in RA patients and evaluated if miRNAs are involved in the modulation of PD-1 expression in NK cells.

Peripheral blood specimens were obtained from 40 RA patients and 20 healthy subjects. NK cells were isolated by negative selection from a pool of peripheral blood mononuclear cells. The frequency of PD-1–expressing NK cells and the expression of PD-1 on NK cells were analyzed by flow cytometry. Real-time PCR was used to measure the expression levels of PD-1 mRNA and miRNAs in the NK cells.

The percentage of the PD-1–expressing NK cells and Mean fluorescence intensity (MFI) of PD-1 expression on the NK cells were significantly higher in the RA cases compared to the controls. The mRNA expression of PD-1 was significantly upregulated in NK cells from RA patients compared to healthy subjects. The expression levels of miR-28, miR-138, and miR-4717 were significantly downregulated in the NK cells from RA patients compared to the healthy group.

In RA, miRNAs probably regulate the NK cell exhaustion process through driving PD-1 expression.