Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation

Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin 1 receptor (IL-1R)-dependent caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6(ΔPMN)) is sufficient to initiate IL-1R-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigated the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1–Ripk3–Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8, and either Ripk3 or Mlkl, strongly protected Ptpn6(ΔPMN) mice. Ptpn6(ΔPMN) neutrophils displayed increased p38 MAP kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor (TNF) production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 MAP kinase activation to control TNF and IL-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3–Mlkl-dependent cell death and concomitant IL-1α/β release.