NOX2-deficient neutrophils facilitate joint inflammation in serum-induced arthritis

Abstract

Abstract Immune-mediated inflammatory arthritis, including rheumatoid arthritis (RA), is a family of chronic inflammatory diseases of joints. NADPH oxidases 2 (NOX2) complex in phagocytes generates high concentrations of ROS to kill the engulfed microbes. Inherited mutations in the subunits of NOX2 result in chronic granulomatous disease (CGD). Subjects with defective NOX2 are susceptible to recurrent infections and a variety of autoimmune conditions. According to our previous studies, NOX2-deficient mice developed more severe immune-mediated arthritis, but depletion of neutrophils suppressed the development of serum-induced arthritis in these mice. Based on the hypothesis that NOX2-deficient neutrophils play a pro-inflammatory role in immune-mediated arthritis, we investigated the activity of neutrophil from joints to facilitate inflammation. We found that there are more neutrophils accumulations in NOX2-deficient joints, compared to WT joints. Both NOX2-deficient /WT neutrophils affected the anti-CD3 and anti-CD28 induced T lymphocyte proliferation, however, NOX2-deficient neutrophils were less suppressive. Moreover, NETs formation and high level of citrullinated histone H3 were detected in joints of NOX2-deficient mice at day 3 of arthritis induction. Furthermore, neutrophils from RA joints were found to suppress the T cell proliferation. Finally, carbonylated protein and total GSH level were lower in synovial fluid of RA patients when compared with those in osteoarthritis joints. Our results implicate that neutrophils may be an important cellular factor that lead to more severe arthritis in the NOX2-deficient subjects.