Interleukin-22 Secreted by NKp44+ Natural Killer Cells Promotes Proliferation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Although CD3-CD56+NKp44+ natural killer (NKp44+NK) cells have been linked to autoimmune diseases including inflammatory bowel disease, ankylosing spondylitis, and primary Sjogren syndrome, the expansion and role of those cells in patients with rheumatoid arthritis (RA) remain less defined. Here, we investigate the proportion and pathogenesis of NKp44+NK cells in patients with RA. The results show NKp44+NK cells significantly expanded in RA peripheral blood and synovial fluid, which were correlated positively with RA disease activity. They also highly expressed in RA synovial tissues and secreted a high concentration of interleukin-22 (IL-22) in vitro. Further, NKp44+NK cells culture supernatant promoted the proliferation of fibroblast-like synoviocytes (FLS) which was blocked by IL-22 antagonist and AG490. Treated with recombination human IL-22, the proliferation and phosphorylation-STAT3 on RA-FLS increased in a dose-dependent manner and time-dependent manner; the progress of which could be blocked by AG490. The present study clarifies the expansion of NKp44+NK cells in the peripheral blood and synovial fluid of patients with RA, 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 FLS in patients with RA.