Loss of PTPN22 promotes intestinal inflammation by compromising granulocyte-mediated anti-bacterial defense.

A single nucleotide polymorphism in protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been associated with the onset of autoimmune disorders, but protects from Crohn's disease. PTPN22-deficiecy in mice promotes intestinal inflammation by modulating lymphocyte function. However, the impact of myeloid PTPN22 in colitis development remains unclear. Here, we demonstrate that PTPN22 in non-lymphoid immune cells is required to protect against T cell transfer-mediated and IL-10 knock-out colitis. Analysis of the intestinal immune landscape demonstrated a marked reduction of granulocyte influx into the inflamed colon in PTPN22-deficient mice. On a molecular level, granulocytes were not only reduced by numbers, but also revealed a defective function. In particular, granulocyte activation and granulocyte-mediated bacteria killing was impaired upon loss of PTPN22, resulting in elevated bacterial burden and translocation beyond the intestinal epithelial barrier in PTPN22-deficient mice. Consistently, antibiotics-induced depletion of bacteria reverted the increased colitis susceptibility in PTPN22-deficient mice, while granulocyte depletion induced a similar colitis phenotype in wild-type mice as observed in PTPN22-deficient mice. In conclusion, our data demonstrate that PTPN22 is essential for adequate granulocyte activation and anti-microbial defense to protect the inflamed intestine from bacterial invasion and exacerbated colitis.