Dataset Information

Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1? in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway.

ABSTRACT: The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1?. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1? in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1? occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1? is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1? production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.

SUBMITTER: Shenderov K

PROVIDER: S-EPMC3935725 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1β in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway.

Shenderov Kevin K Riteau Nicolas N Yip Ronald R Mayer-Barber Katrin D KD Oland Sandy S Hieny Sara S Fitzgerald Pat P Oberst Andrew A Dillon Christopher P CP Green Douglas R DR Cerundolo Vincenzo V Sher Alan A

Journal of immunology (Baltimore, Md. : 1950) 20140131 5

The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1β. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1β in response to LPS stimulation in vitro. Interestingly, the c ...[more]

PMID: 24489101

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Project description:Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.

Dataset Information

Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1? in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway.

Publications

Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1β in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway.

Similar Datasets

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