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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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Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation
Changcheng Zhao1, Devyn D Gillette1, Xinghui Li1
1From the Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599.
The Journal of Biological Chemistry
|May 7, 2014
Summary
Nuclear factor E2-related Factor-2 (Nrf2) drives inflammasome activation, crucial for immune responses. Nrf2 deficiency impairs caspase-1 and IL-1β secretion, highlighting its pro-inflammatory role.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- Inflammasome activation mechanisms, particularly for NLRP3, remain incompletely understood.
- Nuclear factor E2-related Factor-2 (Nrf2) influences cellular redox homeostasis with roles varying by disease.
- The precise mechanism linking Nrf2 to inflammasome activation is undefined.
Purpose of the Study:
- To elucidate the role of Nrf2 in inflammasome activation.
- To investigate the impact of Nrf2 deficiency on inflammasome-mediated responses.
- To determine if Nrf2 influences NLRP3, AIM2, or NLRC4 inflammasome activation.
Main Methods:
- Utilized Nrf2-deficient (Nrf2(-/-)) and wild-type macrophages stimulated with inflammasome activators.
- Assessed caspase-1 and IL-1β maturation and secretion.
- Analyzed apoptosis-associated speck-like protein containing CARD (ASC) speck formation.
- Examined Nrf2 localization and mitochondrial reactive oxygen species (ROS) involvement.
- Employed an alum-induced peritonitis model in Nrf2(-/-) mice.
Main Results:
- Nrf2 deficiency significantly reduced caspase-1 and IL-1β maturation and secretion.
- Nrf2(-/-) macrophages exhibited impaired ASC speck formation with NLRP3 and AIM2 stimuli.
- NLRC4 inflammasome activation was independent of Nrf2.
- Nrf2 was detected in the ASC-enriched cytosolic compartment during NLRP3 activation.
- Mitochondrial ROS-induced NLRP3 activation necessitates Nrf2.
- Nrf2(-/-) mice displayed reduced immune cell recruitment and IL-1β in alum-induced peritonitis.
Conclusions:
- Nrf2 plays a critical role in activating the NLRP3 and AIM2 inflammasomes.
- Nrf2 mediates the maturation and secretion of key inflammatory cytokines like IL-1β.
- This study identifies a significant pro-inflammatory function of Nrf2 through inflammasome activation.
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