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


Mary Speir, Cameron J Nowell, Alyce A Chen, Joanne A O'Donnell, Isaac S Shamie, Paul R Lakin, Akshay A D'Cruz, Roman O Braun, Jeff J Babon, Rowena S Lewis, Meghan Bliss-Moreau, Inbar Shlomovitz, Shu Wang, Louise H Cengia, Anca I Stoica, Razq Hakem, Michelle A Kelliher, Lorraine A O'Reilly, Heather Patsiouras, Kate E Lawlor, Edie Weller, Nathan E Lewis, Andrew W Roberts, Motti Gerlic, and Ben A Croker. 2020. “Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation.” Nat Immunol, 21, 1, Pp. 54-64.


Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate 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 mice. Ptpn6 neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor 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.