Dataset Information

MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1? Independently of Gasdermin-D.

ABSTRACT: Necroptosis is a form of programmed cell death defined by activation of the kinase receptor interacting protein kinase 3 and its downstream effector, the pseudokinase mixed lineage kinase domain-like (MLKL). Activated MLKL translocates to the cell membrane and disrupts it, leading to loss of cellular ion homeostasis. In this study, we use a system in which this event can be specifically triggered by a small-molecule ligand to show that MLKL activation is sufficient to induce the processing and release of bioactive IL-1?. MLKL activation triggers potassium efflux and assembly of the NLRP3 inflammasome, which is required for the processing and activity of IL-1? released during necroptosis. Notably, MLKL activation also causes cell membrane disruption, which allows efficient release of IL-1? independently of the recently described pyroptotic effector gasdermin-D. Taken together, our findings indicate that MLKL is an endogenous activator of the NLRP3 inflammasome, and that MLKL activation provides a mechanism for concurrent processing and release of IL-1? independently of gasdermin-D.

SUBMITTER: Gutierrez KD

PROVIDER: S-EPMC5321867 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D.

Gutierrez Kimberley D KD Davis Michael A MA Daniels Brian P BP Olsen Tayla M TM Ralli-Jain Pooja P Tait Stephen W G SW Gale Michael M Oberst Andrew A

Journal of immunology (Baltimore, Md. : 1950) 20170127 5

Necroptosis is a form of programmed cell death defined by activation of the kinase receptor interacting protein kinase 3 and its downstream effector, the pseudokinase mixed lineage kinase domain-like (MLKL). Activated MLKL translocates to the cell membrane and disrupts it, leading to loss of cellular ion homeostasis. In this study, we use a system in which this event can be specifically triggered by a small-molecule ligand to show that MLKL activation is sufficient to induce the processing and r ...[more]

PMID: 28130493

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Project description:IL-1? is an essential cytokine, but its release needs to be strictly controlled to avoid severe inflammatory manifestations. Lacking a signal sequence, IL-1? does not follow the endoplasmic reticulum-Golgi route. Several pathways have been proposed to mediate its release. One involves the translocation of pro-IL-1? into intracellular vesicles of lysosomal origin that eventually fuse with the plasma membrane. Another exploits pores formed on the plasma membrane upon proteolytic cleavage of gasdermin D (GSDMD). Here we investigated how primary monocytes-the main source of IL-1? in humans-control IL-1? release in response to pro-inflammatory stimuli of increasing intensity and found that two different routes are induced depending on the strength of activation. Triggering of Toll-like receptor 4 (TLR4) by LPS induces slow IL-1? release through LAMP2A+ vesicles. In contrast, the simultaneous stimulation of TLR2, TLR4 and TLR7/8 drives high levels of ROS, GSDMD cleavage and faster IL-1? secretion. Drugs blocking ROS production prevent GSDMD cleavage supporting a role of oxidative stress in GSDMD-mediated secretion. Singly stimulated monocytes undergo apoptosis, whereas triple stimulation triggers pyroptosis, which might amplify inflammation. In both cases, however, IL-1? secretion precedes cell death. Inhibition of caspases 4/5 prevents GSDMD cleavage and pore-mediated secretion, but not vesicular release. The two pathways also display other distinct pharmacologic sensitivities that reflect the underlying mechanisms. Remarkably, single TLR4 stimulation is sufficient to activate massive, GSDMD-mediated IL-1? secretion in monocytes from patients affected by Cryopyrin Associated Periodic Syndrome (CAPS), an autoinflammatory disease linked to NLRP3 mutations. The exaggerated sensitivity to activation correlates with high basal ROS levels in CAPS monocytes. In conclusion, the vesicular pathway limits IL-1? release upon low pathogen load while stronger stimulation or concomitant cell stress induce instead uncontrolled secretion via GSDMD leading to detrimental inflammatory manifestations.

Dataset Information

MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1? Independently of Gasdermin-D.

Publications

MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D.

Similar Datasets

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