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. LawlorEdie Weller, Nathan E. Lewis, Andrew W. Roberts, Motti Gerlic, Ben A. Croker

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-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∆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-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3–Mlkl-dependent cell death and concomitant IL-1α/β release.

Original languageEnglish
Pages (from-to)54-64
Number of pages11
JournalNature Immunology
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Cite this

Speir, M., Nowell, C. J., Chen, A. A., O’Donnell, J. A., Shamie, I. S., Lakin, P. R., D’Cruz, A. A., Braun, R. O., Babon, J. J., Lewis, R. S., Bliss-Moreau, M., Shlomovitz, I., Wang, S., Cengia, L. H., Stoica, A. I., Hakem, R., Kelliher, M. A., O’Reilly, L. A., Patsiouras, H., ... Croker, B. A. (2020). Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation. Nature Immunology, 21(1), 54-64. https://doi.org/10.1038/s41590-019-0550-7