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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
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Cytochrome c Negatively Regulates NLRP3 Inflammasomes
Chong-Shan Shi1, John H Kehrl1
1B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Plos One
|December 29, 2016
Summary
Cytochrome c release during apoptosis limits NLRP3 inflammasome activation by binding NLRP3 and reducing its interactions with cardiolipin and NEK7. This crosstalk between apoptosis and inflammasome pathways suggests a novel regulatory mechanism.
Area of Science:
- Cellular Biology
- Immunology
- Mitochondrial Dynamics
Background:
- Cytochrome c release from mitochondria initiates apoptosis.
- NLRP3 inflammasome activation is crucial for innate immunity.
- Cardiolipin anchors cytochrome c and interacts with NLRP3.
Purpose of the Study:
- To investigate the role of cytosolic cytochrome c in NLRP3 inflammasome activation in macrophages.
- To elucidate the molecular mechanism of cytochrome c's interaction with NLRP3.
Main Methods:
- Protein-protein interaction assays to study binding between cytochrome c and NLRP3.
- Macrophage-based inflammasome activation assays with cytochrome c manipulation.
- In vitro inflammasome reconstitution assays.
Main Results:
- Cytochrome c directly binds to the Leucine-Rich Repeat (LRR) domain of NLRP3.
- Cytochrome c reduces the interaction between NLRP3 and cardiolipin, and between NLRP3 and NEK7.
- Exogenous cytochrome c inhibits NLRP3 inflammasome activation, while its depletion enhances it.
Conclusions:
- Cytochrome c acts as a negative regulator of NLRP3 inflammasome activation.
- A crosstalk exists between the apoptotic (Apaf-1 apoptosome) and inflammatory (NLRP3 inflammasome) pathways mediated by cytochrome c.
- Cytochrome c release during apoptosis serves to dampen NLRP3 inflammasome responses.
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