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Updated: Dec 9, 2025
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Caspase-8 mediates inflammation and disease in rodent malaria
Larissa M N Pereira1,2,3, Patrícia A Assis3, Natalia M de Araújo1,2
1Instituto Rene Rachou, FIOCRUZ-MG, Belo Horizonte, MG, 30190-002, Brazil.
Abstract:
Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1β and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.
Insights
Caspase-8 is key to malaria-induced inflammation and shock. Blocking caspase-8 with inflammasome components like gasdermin-D (GSDM-D) protects against severe malaria, revealing new therapeutic targets.
Area of Science:
- Immunology
- Pathology
- Molecular Biology
Background:
- Inflammasome activation pathways (canonical and non-canonical) have shown limited impact on malaria pathogenesis.
- Understanding the molecular mechanisms driving severe malaria, including systemic inflammation and organ damage, is crucial.
Purpose of the Study:
- To investigate the role of caspase-8 in malaria pathogenesis, particularly in Plasmodium chabaudi and Plasmodium berghei infection models.
- To elucidate the interplay between caspase-8 and inflammasome components (caspases-1/11, gasdermin-D) in malaria-induced mortality and cytokine production.
- To explore the potential role of inflammatory caspases in human malaria.
Main Methods:
- Utilized mouse models of malaria, including Plasmodium chabaudi infection and Plasmodium berghei-induced experimental cerebral malaria (ECM).
- Generated and analyzed mice with combined deficiencies in caspase-8/1/11 or caspase-8/gasdermin-D (GSDM-D).
- Measured levels of tumor necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β) in infected mice.
- Examined caspase activity in monocytes from malaria patients.
Main Results:
- Caspase-8 was identified as a central mediator of systemic inflammation and septic shock in Plasmodium-infected mice.
- Mice lacking both caspase-8 and caspases-1/11, or caspase-8 and GSDM-D, were resistant to lethal malaria and produced less TNFα and IL-1β.
- These findings highlight a complementary yet independent role for caspase-8 and the inflammasome pathway (caspases-1/11/GSDM-D) in malaria pathogenesis.
- Active caspases-1, -4, and -8 were detected in monocytes from malaria patients, suggesting their involvement in human disease.
Conclusions:
- Caspase-8 plays a critical role in mediating lethal inflammation and shock during malaria.
- Targeting caspase-8, potentially in conjunction with inflammasome inhibitors like GSDM-D, offers a promising strategy for treating severe malaria.
- Inflammatory caspases are implicated in the pathogenesis of both experimental and human malaria.
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