Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection
- Author
- Elien Eeckhout (UGent) , Lisa Hamerlinck (UGent) , Veronique Jonckheere (UGent) , Petra Van Damme (UGent) , Geert van Loo (UGent) and Andy Wullaert (UGent)
- Organization
- Project
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- PROPHECY (PROPHECY: Translational control in infection biology: riboproteogenomics of bacterial pathogens)
- Unraveling the heterogeneous nature of host/pathogen encounters and their role in bacterial pathogenesis.
- 3G0C4913
- Evaluating the function and the therapeutic potential of IFN-λ in intestinal carcinogenesis
- Going viral – how does murine norovirus alter intestinal immunity in the host and across generations?
- Dissecting cellular interactions underlying auto-inflammation in Familial Mediterranean Fever
- Investigating the effects of regulatory phosphorylation and linear ubiquitination on Pyrin-mediated auto-inflammatory disorders.
- Revisiting the function and the mechanisms of action of TNF during DSS colitis in conditions of littermate-controlled normalized gut microbiota composition
- Novel mechanisms of inflammation and cell death regulation in autoinflammatory and infectious diseases
- Host-microbe interaction in intestinal homeostasis: unravelling the mechanisms involved in the onset of multiple inflammation-related diseases
- Abstract
- Citrobacter rodentium is an enteropathogen that causes intestinal inflammatory responses in mice reminiscent of the pathology provoked by enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. C. rodentium expresses various virulence factors that target specific signaling proteins involved in executing apoptotic, necroptotic and pyroptotic cell death, suggesting that each of these distinct cell death modes performs essential host defense functions that the pathogen aims to disturb. However, the relative contributions of apoptosis, necroptosis and pyroptosis in protecting the host against C. rodentium have not been elucidated. Here we used mice with single or combined deficiencies in essential signaling proteins controlling apoptotic, necroptotic or pyroptotic cell death to reveal the roles of these cell death modes in host defense against C. rodentium. Gastrointestinal C. rodentium infections in mice lacking GSDMD and/or MLKL showed that both pyroptosis and necroptosis were dispensable for pathogen clearance. In contrast, while RIPK3-deficient mice showed normal C. rodentium clearance, mice with combined caspase-8 and RIPK3 deficiencies failed to clear intestinal pathogen loads. Although this demonstrated a crucial role for caspase-8 signaling in establishing intestinal host defense, Casp8(-/-)Ripk3(-/-) mice remained capable of preventing systemic pathogen persistence. This systemic host defense relied on inflammasome signaling, as Casp8(-/-)Ripk3(-/-) mice with combined caspase-1 and -11 deletion succumbed to C. rodentium infection. Interestingly, although it is known that C. rodentium can activate the non-canonical caspase-11 inflammasome, selectively disabling canonical inflammasome signaling by single caspase-1 deletion sufficed to render Casp8(-/-)Ripk3(-/-) mice vulnerable to C. rodentium-induced lethality. Moreover, Casp8(-/-)Ripk3(-/-) mice lacking GSDMD survived a C. rodentium infection, suggesting that pyroptosis was not crucial for the protective functions of canonical inflammasomes in these mice. Taken together, our mouse genetic experiments revealed an essential cooperation between caspase-8 signaling and GSDMD-independent canonical inflammasome signaling to establish intestinal and systemic host defense against gastrointestinal C. rodentium infection.
- Keywords
- Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology, EPITHELIAL-CELLS, ACTIVATION, MICE, EXPRESSION, DEFICIENT, RECEPTORS, APOPTOSIS, PROTECTS, DAMAGE, TOLL
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01H3FNNZ1J76ABA5VX5DVB1K08
- MLA
- Eeckhout, Elien, et al. “Gasdermin D Independent Canonical Inflammasome Responses Cooperate with Caspase-8 to Establish Host Defense against Gastrointestinal Citrobacter Rodentium Infection.” CELL DEATH & DISEASE, vol. 14, no. 4, 2023, doi:10.1038/s41419-023-05801-4.
- APA
- Eeckhout, E., Hamerlinck, L., Jonckheere, V., Van Damme, P., van Loo, G., & Wullaert, A. (2023). Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection. CELL DEATH & DISEASE, 14(4). https://doi.org/10.1038/s41419-023-05801-4
- Chicago author-date
- Eeckhout, Elien, Lisa Hamerlinck, Veronique Jonckheere, Petra Van Damme, Geert van Loo, and Andy Wullaert. 2023. “Gasdermin D Independent Canonical Inflammasome Responses Cooperate with Caspase-8 to Establish Host Defense against Gastrointestinal Citrobacter Rodentium Infection.” CELL DEATH & DISEASE 14 (4). https://doi.org/10.1038/s41419-023-05801-4.
- Chicago author-date (all authors)
- Eeckhout, Elien, Lisa Hamerlinck, Veronique Jonckheere, Petra Van Damme, Geert van Loo, and Andy Wullaert. 2023. “Gasdermin D Independent Canonical Inflammasome Responses Cooperate with Caspase-8 to Establish Host Defense against Gastrointestinal Citrobacter Rodentium Infection.” CELL DEATH & DISEASE 14 (4). doi:10.1038/s41419-023-05801-4.
- Vancouver
- 1.Eeckhout E, Hamerlinck L, Jonckheere V, Van Damme P, van Loo G, Wullaert A. Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection. CELL DEATH & DISEASE. 2023;14(4).
- IEEE
- [1]E. Eeckhout, L. Hamerlinck, V. Jonckheere, P. Van Damme, G. van Loo, and A. Wullaert, “Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection,” CELL DEATH & DISEASE, vol. 14, no. 4, 2023.
@article{01H3FNNZ1J76ABA5VX5DVB1K08,
abstract = {{Citrobacter rodentium is an enteropathogen that causes intestinal inflammatory responses in mice reminiscent of the pathology provoked by enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. C. rodentium expresses various virulence factors that target specific signaling proteins involved in executing apoptotic, necroptotic and pyroptotic cell death, suggesting that each of these distinct cell death modes performs essential host defense functions that the pathogen aims to disturb. However, the relative contributions of apoptosis, necroptosis and pyroptosis in protecting the host against C. rodentium have not been elucidated. Here we used mice with single or combined deficiencies in essential signaling proteins controlling apoptotic, necroptotic or pyroptotic cell death to reveal the roles of these cell death modes in host defense against C. rodentium. Gastrointestinal C. rodentium infections in mice lacking GSDMD and/or MLKL showed that both pyroptosis and necroptosis were dispensable for pathogen clearance. In contrast, while RIPK3-deficient mice showed normal C. rodentium clearance, mice with combined caspase-8 and RIPK3 deficiencies failed to clear intestinal pathogen loads. Although this demonstrated a crucial role for caspase-8 signaling in establishing intestinal host defense, Casp8(-/-)Ripk3(-/-) mice remained capable of preventing systemic pathogen persistence. This systemic host defense relied on inflammasome signaling, as Casp8(-/-)Ripk3(-/-) mice with combined caspase-1 and -11 deletion succumbed to C. rodentium infection. Interestingly, although it is known that C. rodentium can activate the non-canonical caspase-11 inflammasome, selectively disabling canonical inflammasome signaling by single caspase-1 deletion sufficed to render Casp8(-/-)Ripk3(-/-) mice vulnerable to C. rodentium-induced lethality. Moreover, Casp8(-/-)Ripk3(-/-) mice lacking GSDMD survived a C. rodentium infection, suggesting that pyroptosis was not crucial for the protective functions of canonical inflammasomes in these mice. Taken together, our mouse genetic experiments revealed an essential cooperation between caspase-8 signaling and GSDMD-independent canonical inflammasome signaling to establish intestinal and systemic host defense against gastrointestinal C. rodentium infection.}},
articleno = {{282}},
author = {{Eeckhout, Elien and Hamerlinck, Lisa and Jonckheere, Veronique and Van Damme, Petra and van Loo, Geert and Wullaert, Andy}},
issn = {{2041-4889}},
journal = {{CELL DEATH & DISEASE}},
keywords = {{Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology,EPITHELIAL-CELLS,ACTIVATION,MICE,EXPRESSION,DEFICIENT,RECEPTORS,APOPTOSIS,PROTECTS,DAMAGE,TOLL}},
language = {{eng}},
number = {{4}},
pages = {{16}},
title = {{Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection}},
url = {{http://doi.org/10.1038/s41419-023-05801-4}},
volume = {{14}},
year = {{2023}},
}
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