Background/Purpose: Although CD3-CD56+NKp44+ natural Killer cells (NKp44+NK cells) have been linked to autoimmune diseases including inflammatory bowel disease, ankylosing spondylitis, and primary Sjogren’s syndrome, the expansion and role of those cells in rheumatoid arthritis (RA) remain less defined. Here, we investigate the proportion of NKp44+NK cells in RA patients and examine whether those cells play a role in the pathogenesis of RA.

Methods: The frequency of NKp44+NK cells using flow cytometric analysis in peripheral blood (PB) or synovial fluid (SF) and their association with disease activity were examined in RA patients and controls. The expansion of those cells in RA and OA synovial tissues was also detected by dual-labeling immunofluorescence. And then, the concentration of IL -22 secreted by NKp44+NK cells was examined by Enzyme-linked immunosorbent assay. Eventually, the proliferation of fibroblast-like synoviocytes (FLS) and detection of IL-22-dependent signal pathway were examined by methyl thiazolyl tetrazolium and western blot analysis respectively after the treatment of NKp44+NK cells culture supernatant, IL-22 antagonist, recombinant human (rh) IL-22, or a selective signalling pathways inhibitor (AG490).

Results: When compared with controls, NKp44+NK cells significantly expanded in RA PB (3.1±2.4% vs 0.5±0.8%; p<0.001) and SF (7.1±4.2% vs 0.9±1.2%; p<0.001), which were correlated positively with disease activity scroe in 28 joints and clinical disease activity index (p<0.001). Those cells also highly expressed in RA synovial tissues, but were not detected in OA synovial tissues. It provided a source of IL-22 with high concentrations (5826.5±284.2pg/ml). Further, NKp44+NK cells culture supernatant promoted the proliferation of FLS which was blocked by IL-22 antagonist. Treated with rhIL-22, the proliferation and phosphorylation-STAT3 on RA-FLS increased in a dose dependent manner and time dependent manner respectively, the progress of which could be blocked by AG490.

Conclusion: The present study clarifies the expansion of NKp44+NK cells in the PB and SF of RA patients, especially in the synovial tissues of RA for the first time. STAT3 is an essential pathway in mediating the effects of IL-22 secreted by NKp44+NK cells on the proliferation of synovium in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-22-secreted-by-nkp44nk-cells-promote-the-proliferation-of-synovium-in-patients-with-rheumatoid-arthritis-by-activation-of-stat3/