| First Author | Speir M | Year | 2020 |
| Journal | Nat Immunol | Volume | 21 |
| Issue | 1 | Pages | 54-64 |
| PubMed ID | 31819256 | Mgi Jnum | J:290374 |
| Mgi Id | MGI:6435499 | Doi | 10.1038/s41590-019-0550-7 |
| Citation | Speir M, et al. (2020) Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation. Nat Immunol 21(1):54-64 |
| abstractText | 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(PMN)) 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-1alpha/beta 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(PMN) mice. Ptpn6(PMN) 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-1alpha/beta expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1alpha/beta release. |
