Background/Purpose: Rheumatoid arthritis (RA) synovial fluid exhibits high levels of type 1 interferons (IFN). Type 1 IFN may exert potent anti-inflammatory effects, since a TLR3 agonist suppresses inflammatory arthritis in a type 1 IFN-dependent manner. PTPN22,  encoding Lymphoid Tyrosine Phosphatase (Lyp), is a “risk” gene for RA. A PTPN22 disease-associated variant encodes an R620W substitution-bearing protein “LypW”. We showed previously that PTPN22 promotes Toll-like receptor (TLR) signaling and type 1 IFN production. Further, we found that LypW exhibits reduced function in poly(I:C)-mediated suppression of inflammatory arthritis in the K/BxN “serum-transfer” arthritis model. TLR9 agonists can also suppress arthritis through an unknown mechanism. We tested the hypothesis that PTPN22 is required for TLR9 agonist-driven amelioration of arthritis.

Methods: Serum-transfer arthritis was induced in control or Ptpn22^-/- mice by intraperitoneal injection of K/BxN mouse serum. Mice were then injected with ODN 1668 (10 nmol), a CpG oligonucleotide agonist of TLR9. Arthritis scores were monitored. Synovial RNA was assayed for type 1 interferon and interferon-dependent gene expression via RT-qPCR.

Results: Confirming previous reports, ODN 1668 treatment ameliorated serum-transfer arthritis in control mice. However, Ptpn22^-/- mice exhibited diminished suppressive response to ODN 1668. Reduced arthritis amelioration in Ptpn22^-/- mice correlated with impaired TLR9 induction of Ifna4 and Cxcl10 (type 1 IFN-dependent chemokines) in synovium (Figure 1).

Figure 1: Mice (n = 3 per group) were injected with K/BxN serum together with ODN 1668 or vehicle alone. Arthritis severity scores (mean± SEM) are shown. WT, wild-type; KO, Ptpn22^-/-.

Figure 2: Expression of Ifna4 and the IFN-inducible gene Cxcl10 in synovium at day 11 post injection of serum was determined by qPCR.

Conclusion: Ptpn22 is required for CpG-induced amelioration of inflammatory arthritis, and for upregulation of type 1 IFN-dependent genes in synovium. These data support a model wherein Ptpn22 exerts anti-inflammatory effects by promoting TLR signals that induce type 1 IFN and type I IFN-dependent genes.