Neutrophils are essential for the host’s defence against infections, but also play a key role in acute and chronic inflammation. The PTPN22 gene (non-receptor tyrosine phosphatase type 22) encodes lymphocyte-specific tyrosine phosphatase (Lyp). A single-nucleotide polymorphism in PTPN22, rs2476601 (R620W), has been associated with several autoimmune diseases, including rheumatoid arthritis (RA).
In this study, we investigated the role of Lyp in the potentiation of TNF-α-induced production of reactive oxygen species (ROS) by neutrophils, as well as in the development of arthritis, using novel selective Lyp inhibitors. The results show that selective Lyp inhibitors (IC-11 and compound 8b) inhibit the TNF-α-induced potentiation of superoxide anion production in neutrophils. Furthermore, TNF-α induces an increase in Lyp expression in human neutrophils isolated from healthy donors.
Selective Lyp inhibitors block the main pathways involved in the potentiation of ROS production, notably TNF-α-induced phosphorylation of p47phox at Ser345, phosphorylation of ERK1/2 and activation of Pin1. Interestingly, Lyp expression is increased in neutrophils isolated from the synovial fluid of patients with RA, and Lyp inhibitors (IC-11 and compound 8b) prevent excessive ROS production by these neutrophils.
Furthermore, in mice, IC-11 significantly reduces arthritis induced by anti-collagen antibodies. These results show that Lyp expression is increased in inflammatory neutrophils, that Lyp is involved in the excessive production of ROS induced by TNF-α in neutrophils, and that its inhibition protects mice against arthritis. Thus, inhibiting Lyp could represent a therapeutic strategy for rheumatoid arthritis.
