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Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection
Felicia Hui Min Chan1, Hui Wen Yeap1, Zonghan Liu1
1Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
Abstract:
Macrophages express pattern recognition and cytokine receptors that mediate proinflammatory signal transduction pathways to combat microbial infection. To retaliate against such responses, pathogenic microorganisms have evolved multiple strategies to impede innate immune signaling. Recent studies demonstrated that YopJ suppression of TAK1 signaling during Yersinia pseudotuberculosis infection promotes the assembly of a RIPK1-dependent death-inducing complex that enables caspase-8 to directly cleave and activate gasdermin D (GSDMD). However, whether and how macrophages respond to Yersinia infection in the absence of YopJ or caspase-8 activity remains unclear. Here, we demonstrate that loss of YopJ or its catalytic activity triggers non-canonical inflammasome activation in macrophages and that caspase-11 is required to restrict the bacterial burden in vivo. Under conditions of low caspase-8 activity, wild-type Y. pseudotuberculosis invades macrophages and accesses the cytosol, leading to non-canonical inflammasome activation. Thus, our study highlights the plasticity of death pathways to ensure GSDMD activation during Yersinia infection.
Insights
Yersinia pseudotuberculosis infection triggers inflammasome activation in macrophages lacking YopJ or caspase-8. Caspase-11 is crucial for controlling bacterial burden in vivo, highlighting immune pathway plasticity.
Area of Science:
- Immunology
- Microbiology
- Cellular Biology
Background:
- Macrophages utilize pattern recognition and cytokine receptors for innate immune responses against microbial infections.
- Pathogens like Yersinia pseudotuberculosis have evolved mechanisms, such as YopJ effector protein, to suppress host immune signaling pathways.
- YopJ inhibits TAK1 signaling, promoting RIPK1-dependent complex assembly and caspase-8 activation of gasdermin D (GSDMD), leading to pyroptosis.
Purpose of the Study:
- To investigate macrophage responses to Yersinia infection in the absence of YopJ or caspase-8.
- To elucidate the role of caspase-11 in controlling bacterial burden during Yersinia infection.
- To understand the plasticity of cell death pathways in ensuring GSDMD activation.
Main Methods:
- Utilized Yersinia pseudotuberculosis infection models in macrophages.
- Assessed inflammasome activation, specifically non-canonical inflammasome pathways.
- Investigated the role of YopJ, caspase-8, and caspase-11 in macrophage response and bacterial clearance in vivo.
Main Results:
- Loss of YopJ or its catalytic activity induces non-canonical inflammasome activation in macrophages.
- Caspase-11 is essential for restricting Yersinia bacterial burden in vivo.
- Yersinia pseudotuberculosis invasion into the macrophage cytosol triggers non-canonical inflammasome activation when caspase-8 activity is low.
Conclusions:
- Macrophage response to Yersinia infection exhibits plasticity, ensuring GSDMD activation through alternative pathways.
- Non-canonical inflammasome activation, dependent on caspase-11, is a critical host defense mechanism against Yersinia.
- Understanding these pathways offers insights into host-pathogen interactions and potential therapeutic targets.
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