Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation

Carla M. Cuda, Alexander V. Misharin, Angelica K. Gierut, Rana Saber, G. Kenneth Haines, Jack Hutcheson, Stephen M. Hedrick, Chandra Mohan, G. Scott Budinger, Christian Stehlik, Harris Perlman

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Caspase-8, an executioner enzyme in the death receptor pathway, was shown to initiate apoptosis and suppress necroptosis. In this study, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs): DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the lifespan of DCs but instead leads to an enhanced intrinsic activation and, subsequently, more mature and autoreactive lymphocytes. Uncontrolled TLR activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, because deletion of the TLR-signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell type-specific manner and acts uniquely in DCs to maintain tolerance.

Original languageEnglish (US)
Pages (from-to)5548-5560
Number of pages13
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Cuda, C. M., Misharin, A. V., Gierut, A. K., Saber, R., Haines, G. K., Hutcheson, J., Hedrick, S. M., Mohan, C., Budinger, G. S., Stehlik, C., & Perlman, H. (2014). Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. Journal of Immunology, 192(12), 5548-5560. https://doi.org/10.4049/jimmunol.1400122