Abstract
BackgroundNeutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA). It has recently been reported that in addition to T helper (Th) 17 cells, other cells, including neutrophils, produce IL-17A, an important inflammatory cytokine involved in the pathogenesis of RA. The purpose of this study was to examine the presence of interleukin 17A-producing neutrophils in patients with RA.MethodsWe performed a cross-sectional study including 106 patients with RA and 56 healthy individuals. Whole peripheral blood cells were analyzed by flow cytometry to identify CD66b+ CD177+ IL-17A+ neutrophils and CD3+ CD4+ IL-17A+ T cells. Serum levels of IL-17A and IL-6 were measured by means of cytometry bead array (CBA). In purified neutrophils, mRNA levels of IL-17 and RORγ were measured by RT-PCR. In addition, purified neutrophils from patients and healthy controls were stimulated with the cytokines IL-6 and IL-23 to evaluate differences in their capacity to produce IL-17A.ResultsNeutrophils from RA patients expressed IL-17 and RORγ mRNA. Consequently, these cells also expressed IL-17A. Serum IL-17A levels but not Th17 cell numbers were increased in RA patients. Neutrophils positive for cytoplasmic IL-17A were more abundant in patients with RA (mean 1.2 ± 3.18%) than in healthy individuals (mean 0.07 ± 0.1%) (p < 0.0001). Although increased IL-17A+ neutrophil numbers were present in RA patients regardless of disease activity (mean 6.5 ± 5.14%), they were more frequent in patients with a more recent diagnosis (mean time after disease onset 3.5 ± 4.24 years). IL-6 and IL-23 induced the expression of RORγ but failed to induce IL-17A expression by neutrophils from RA patients and healthy individuals after a 3 h stimulation.ConclusionIL-17A-producing neutrophils are increased in some RA patients, which are not related to disease activity but have an increased frequency in patients with recent-onset disease. This finding suggests that IL-17A-producing neutrophils play an early role in the development of RA.
Highlights
Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA)
IL-17A levels are increased in the synovial fluid and serum [5,6,7], and Th17 cells are enriched in the synovial membrane of RA patients [6]
We studied the frequency of IL-17A+ circulating neutrophils in RA patients and healthy controls
Summary
Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA). It has recently been reported that in addition to T helper (Th) 17 cells, other cells, including neutrophils, produce IL-17A, an important inflammatory cytokine involved in the pathogenesis of RA. The purpose of this study was to examine the presence of interleukin 17A-producing neutrophils in patients with RA. Tumor necrosis factor (TNF) and interleukin (IL)-6 appear to play a major role in the pathogenesis of tissue damage in RA, as evidenced by a decrease of disease activity after blocking of these cytokines [2]. Other cytokines involved in the pathogenesis of RA include interferon (IFN)-γ and IL-17, which are the major effector cytokines of the Th1 and Th17 subsets of CD4+ T lymphocytes, respectively [3, 4]. Preliminary clinical trials targeting IL-17A in RA have shown some clinical benefits, these positive results have yet to be confirmed in large-scale clinical trials [4, 9, 10]
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