Related Experiment Video
Updated: Sep 1, 2025
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b
Xiang Li1,2, Peipei Zhang2, Zhiyong Yin1
1Department of Physics and Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen 361005, China.
Abstract:
Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new "coexisting" state in single cells is proposed when GSDMD acts as the driving force of the landscape. The "seesaw model" is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.
Insights
Inflammasome signaling regulates cell death modes like pyroptosis and apoptosis. Caspase-1 and GSDMD levels control these switches, offering new disease control strategies.
Area of Science:
- Immunology
- Cell Biology
- Computational Biology
Background:
- Inflammasomes are key innate immune complexes defending against pathogens.
- Inflammasome signaling is linked to COVID-19, but regulatory mechanisms remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms of inflammasome signaling, specifically NLRP1b inflammasome.
- To understand how cell death modes are switched between pyroptosis and apoptosis.
Main Methods:
- Combined mathematical modeling with experimental analysis of NLRP1b inflammasome signaling.
- Investigated the roles of caspase-1 and GSDMD in regulating cell death pathways.
Main Results:
- Caspase-1 and GSDMD expression levels individually switch cell death modes from pyroptosis to apoptosis.
- Distinct thresholds and pathway choices for caspase-1 and GSDMD in switching death modes were identified.
- A novel 'coexisting' cell death state was proposed, described by a 'seesaw model' controlled by caspase-1 or GSDMD.
Conclusions:
- The study reveals critical insights into NLRP1b inflammasome signaling and cell death mode switching.
- Findings provide potential strategies for developing targeted disease control interventions.
Related Concept Videos
01:24Caspases
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway
01:30Apoptosis
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...