Experimental colitis in IL-10-deficient mice ameliorates in the absence of PTPN22.

Interleukin (IL)-10 plays a key role in controlling intestinal inflammation. IL-10-deficient mice and patients with mutations in IL-10 or its receptor, IL-10R, show increased susceptibility to inflammatory bowel diseases (IBD). Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) controls immune cell activation and the equilibrium between regulatory and effector T cells, playing an important role in controlling immune homoeostasis of the gut. Here, we examined the role of PTPN22 in intestinal inflammation of IL-10-deficient (IL-10^-/- ) mice. We crossed IL-10^-/- mice with PTPN22^-/- mice to generate PTPN22^-/- IL-10^-/- double knock-out mice and induced colitis with dextran sodium sulphate (DSS). In line with previous reports, DSS-induced acute and chronic colitis was exacerbated in IL-10^-/- mice compared to wild-type (WT) controls. However, PTPN22^-/- IL-10^-/- double knock-out mice developed milder disease compared to IL-10^-/- mice. IL-17-promoting innate cytokines and T helper type 17 (Th17) cells were markedly increased in PTPN22^-/- IL-10^-/- mice, but did not provide a protctive function. CXCL1/KC was also increased in PTPN22^-/- IL-10^-/- mice, but therapeutic injection of CXCL1/KC in IL-10^-/- mice did not ameliorate colitis. These results show that PTPN22 promotes intestinal inflammation in IL-10-deficient mice, suggesting that therapeutic targeting of PTPN22 might be beneficial in patients with IBD and mutations in IL-10 and IL-10R.

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