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

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.

SUBMITTER: Cuda CM

PROVIDER: S-EPMC4074511 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Cuda Carla M CM Misharin Alexander V AV Gierut Angelica K AK Saber Rana R Haines G Kenneth GK Hutcheson Jack J Hedrick Stephen M SM Mohan Chandra C Budinger G Scott GS Stehlik Christian C Perlman Harris H

Journal of immunology (Baltimore, Md. : 1950) 20140507 12

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 ...[more]

PMID: 24808358

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Project description:BackgroundLow back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration.MethodsIn this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients' normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo.ResultsRIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients' degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1.ConclusionsThese results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality.

Dataset Information

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

Publications

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

Similar Datasets

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