Wip1-deficient neutrophils significantly promote intestinal ischemia/reperfusion injury in mice.

Wip1 is a serine/threonine protein phosphatase which plays a critical role in neutrophil development and maturation. In the present study, we used a neutrophil-dependent model of intestinal ischemia/reperfusion (I/R) injury to identify the role of Wip1 in neutrophil function under the condition of oxidative stress and inflammation. Wip1-deficient mice displayed more severe intestinal I/R injury with increased infiltration of neutrophils and higher expression of chemokines like CXCL-1, CXCL-2 and CCL-2, as well as inflammatory cytokine like TNF-alpha and IL-17. Studies in Wip1KO -> WT full hematopoietic chimera mice showed that Wip1 intrinsically regulated the function of immune cells after intestinal I/R injury. Through adoptive transfer of neutrophils from WT mice or mice with deficiency of IL-17, IL-17/Wip1 or Wip1, we demonstrated that Wip1KO neutrophils produced more IL-17 and eventually led to more severe intestinal I/R injury. Thus, our findings identify Wip1 as an intrinsic negative regulator of neutrophil inflammation in intestinal I/R injury process.