PTPN22 Is a Critical Regulator of Fcγ Receptor-Mediated 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 nonreceptor 22 (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 in this article that neutrophil effector functions, including adhesion, production of 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, which are required to enable full FcγR-induced activation, pointing to an important role for this molecule in neutrophil function.
Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; Sonja.Vermeren@ed.ac.uk Mohini.Gray@ed.ac.uk.
Sonja
0000-0002-8460-0884
S
Vermeren
Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Katherine
K
Miles
Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Julia Y
JY
Chu
Institute for Genetics and Molecular Medicine, Edinburgh EH4 2XU, United Kingdom; and.
Donald
0000-0002-4451-4375
D
Salter
Institute of Immunology and Infection Research, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
Rose
0000-0001-9816-2638
R
Zamoyska
Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; Sonja.Vermeren@ed.ac.uk Mohini.Gray@ed.ac.uk.
Mohini
0000-0002-7622-214X
M
Gray
D000818:Animals; D000936:Antigen-Antibody Complex; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002448:Cell Adhesion; D015550:Cell Degranulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000936:Antigen-Antibody Complex; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse