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

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.