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

28 Citations (Scopus)

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

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Caspase 8
Dendritic Cells
Autoimmunity
Autoimmune Lymphoproliferative Syndrome
Death Domain Receptors
Cell Death
Lymphocytes
Apoptosis
Enzymes

ASJC Scopus subject areas

  • Immunology

Cite this

Cuda, C. M., Misharin, A. V., Gierut, A. K., Saber, R., Haines, G. K., Hutcheson, J., ... 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

Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. / Cuda, Carla M.; Misharin, Alexander V.; Gierut, Angelica K.; Saber, Rana; Haines, G. Kenneth; Hutcheson, Jack; Hedrick, Stephen M.; Mohan, Chandra; Budinger, G. Scott; Stehlik, Christian; Perlman, Harris.

In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 5548-5560.

Research output: Contribution to journalArticle

Cuda, CM, Misharin, AV, Gierut, AK, Saber, R, Haines, GK, Hutcheson, J, Hedrick, SM, Mohan, C, Budinger, GS, Stehlik, C & Perlman, H 2014, 'Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation', Journal of Immunology, vol. 192, no. 12, pp. 5548-5560. https://doi.org/10.4049/jimmunol.1400122
Cuda CM, Misharin AV, Gierut AK, Saber R, Haines GK, Hutcheson J et al. Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. Journal of Immunology. 2014 Jun 15;192(12):5548-5560. https://doi.org/10.4049/jimmunol.1400122
Cuda, Carla M. ; Misharin, Alexander V. ; Gierut, Angelica K. ; Saber, Rana ; Haines, G. Kenneth ; Hutcheson, Jack ; Hedrick, Stephen M. ; Mohan, Chandra ; Budinger, G. Scott ; Stehlik, Christian ; Perlman, Harris. / Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. In: Journal of Immunology. 2014 ; Vol. 192, No. 12. pp. 5548-5560.
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