PTPN22 is a critical regulator of Fcg receptor 1mediated neutrophil activation

Neutrophils act as a first line of defense against bacterial and fungal infections but they are also important effectors of acute and chronic inflammation. Genome wide association studies have established that the gene encoding the protein tyrosine phosphatase PTPN22 makes an important contribution to susceptibility to
autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show here that neutrophil effector functions, including adhesion, production of 34 reactive oxygen species and degranulation induced by immobilized immune complexes were reduced in Ptpn22-/- neutrophils. Tyrosine phosphorylation of Lyn and Syk was altered in Ptpn22-/- neutrophils. On stimulation with immobilized immune complexes, Ptpn22-/- neutrophils manifested reduced activation of key signaling intermediates. Ptpn22-/- mice were protected from immune complex mediated arthritis, induced by the transfer of arthritogenic serum. In contrast, in vivo neutrophil recruitment following thioglycollate induced peritonitis and in vitro chemotaxis were not affected by lack of PTPN22. Our data suggest an important role for PTPN22-dependent dephosphorylation events, that are required to enable full Fcγ receptor induced activation, pointing to an important role for this molecule in neutrophil function.