Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection
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 signa...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05801-4 |
| _version_ | 1797840783800270848 |
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| author | Elien Eeckhout Lisa Hamerlinck Veronique Jonckheere Petra Van Damme Geert van Loo Andy Wullaert |
| author_facet | Elien Eeckhout Lisa Hamerlinck Veronique Jonckheere Petra Van Damme Geert van Loo Andy Wullaert |
| author_sort | Elien Eeckhout |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T16:20:19Z |
| format | Article |
| id | doaj.art-5979f518de434555b00d37dbbe8ecd50 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T16:20:19Z |
| publishDate | 2023-04-01 |
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| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-5979f518de434555b00d37dbbe8ecd502023-04-23T11:29:44ZengNature Publishing GroupCell Death and Disease2041-48892023-04-0114411610.1038/s41419-023-05801-4Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infectionElien Eeckhout0Lisa Hamerlinck1Veronique Jonckheere2Petra Van Damme3Geert van Loo4Andy Wullaert5Department of Internal Medicine and Paediatrics, Ghent UniversityDepartment of Internal Medicine and Paediatrics, Ghent UniversityiRIP Unit, Laboratory of Microbiology, Department of Biochemistry and Microbiology, Ghent UniversityiRIP Unit, Laboratory of Microbiology, Department of Biochemistry and Microbiology, Ghent UniversityVIB-UGent Center for Inflammation Research, VIBDepartment of Internal Medicine and Paediatrics, Ghent UniversityAbstract 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.https://doi.org/10.1038/s41419-023-05801-4 |
| spellingShingle | Elien Eeckhout Lisa Hamerlinck Veronique Jonckheere Petra Van Damme Geert van Loo Andy Wullaert Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection Cell Death and Disease |
| title | Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection |
| title_full | Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection |
| title_fullStr | Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection |
| title_full_unstemmed | Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection |
| title_short | Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection |
| title_sort | gasdermin d independent canonical inflammasome responses cooperate with caspase 8 to establish host defense against gastrointestinal citrobacter rodentium infection |
| url | https://doi.org/10.1038/s41419-023-05801-4 |
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