TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B
Abstract Clostridioides difficile, a spore-forming anaerobic bacterium, is the primary cause of hospital antibiotic-associated diarrhea. Key virulence factors, toxins A (TcdA) and B (TcdB), significantly contribute to C. difficile infection (CDI). Yet, the specific impact of these toxins, particular...
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| Format: | Article |
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BMC
2025-01-01
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| Series: | Journal of Inflammation |
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| Online Access: | https://doi.org/10.1186/s12950-024-00425-7 |
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| author | Dvison de Melo Pacífico Deiziane Viana da Silva Costa Maria Lucianny Lima Barbosa Conceição Silva Martins Rebouças Simone de Goes Simonato Cirle Alcantara Warren Maria Luana Gaudencio dos Santos Morais Renata Ferreira de Carvalho Leitao Gerly Anne de Castro Brito |
| author_facet | Dvison de Melo Pacífico Deiziane Viana da Silva Costa Maria Lucianny Lima Barbosa Conceição Silva Martins Rebouças Simone de Goes Simonato Cirle Alcantara Warren Maria Luana Gaudencio dos Santos Morais Renata Ferreira de Carvalho Leitao Gerly Anne de Castro Brito |
| author_sort | Dvison de Melo Pacífico |
| collection | DOAJ |
| description | Abstract Clostridioides difficile, a spore-forming anaerobic bacterium, is the primary cause of hospital antibiotic-associated diarrhea. Key virulence factors, toxins A (TcdA) and B (TcdB), significantly contribute to C. difficile infection (CDI). Yet, the specific impact of these toxins, particularly on enteric glial cells (EGCs), still needs to be fully understood. This study examines the role of the transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable channel, in the inflammatory response and apoptosis of EGCs induced by TcdA and TcdB and evaluates TRPV4 expression in the cecum and colon of infected mice. EGCs were treated with TcdA (50ng/mL) or TcdB (1ng/mL) for 18 h, with or without the TRPV4 antagonist RN-1734 (100 µM), to assess TRPV4 gene and protein levels, inflammatory markers, and cell death. C. difficile infected mice were euthanized on day 3 post-infection for TRPV4 expression in the cecum and colon. Findings reveal that EGCs naturally express TRPV4, increasing its expression by TcdA and TcdB exposure. CDI significantly upregulates TRPV4 in the cecum and colon’s submucosal and myenteric plexus regions. TRPV4 mediates TNF-α release in EGCs and is partially involved in the increase in IL-6 gene expression triggered by these toxins. Our results highlight TRPV4’s role in triggering EGC apoptosis via caspase 3 activation and inhibiting the reduction of Bcl-2, an anti-apoptotic protein in EGCs caused by C. difficile toxins. These results highlight TRPV4’s significant role in CDI pathogenesis and its potential as a therapeutic target to counteract the detrimental effects of C. difficile toxins on enteric glia. |
| format | Article |
| id | doaj-art-48f14da6c9ee4f5c842036af9f7e7d62 |
| institution | Kabale University |
| issn | 1476-9255 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Inflammation |
| spelling | doaj-art-48f14da6c9ee4f5c842036af9f7e7d622025-01-19T12:10:18ZengBMCJournal of Inflammation1476-92552025-01-0122111610.1186/s12950-024-00425-7TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and BDvison de Melo Pacífico0Deiziane Viana da Silva Costa1Maria Lucianny Lima Barbosa2Conceição Silva Martins Rebouças3Simone de Goes Simonato4Cirle Alcantara Warren5Maria Luana Gaudencio dos Santos Morais6Renata Ferreira de Carvalho Leitao7Gerly Anne de Castro Brito8Department of Morphology, Faculty of Medicine, Federal University of CearáDivision of Infectious Diseases and International Health, University of VirginiaDepartment of Morphology, Faculty of Medicine, Federal University of CearáDepartment of Morphology, Faculty of Medicine, Federal University of CearáDepartment of Morphology, Faculty of Medicine, Federal University of CearáDivision of Infectious Diseases and International Health, University of VirginiaDepartment of Morphology, Faculty of Medicine, Federal University of CearáDepartment of Morphology, Faculty of Medicine, Federal University of CearáDepartment of Morphology, Faculty of Medicine, Federal University of CearáAbstract Clostridioides difficile, a spore-forming anaerobic bacterium, is the primary cause of hospital antibiotic-associated diarrhea. Key virulence factors, toxins A (TcdA) and B (TcdB), significantly contribute to C. difficile infection (CDI). Yet, the specific impact of these toxins, particularly on enteric glial cells (EGCs), still needs to be fully understood. This study examines the role of the transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable channel, in the inflammatory response and apoptosis of EGCs induced by TcdA and TcdB and evaluates TRPV4 expression in the cecum and colon of infected mice. EGCs were treated with TcdA (50ng/mL) or TcdB (1ng/mL) for 18 h, with or without the TRPV4 antagonist RN-1734 (100 µM), to assess TRPV4 gene and protein levels, inflammatory markers, and cell death. C. difficile infected mice were euthanized on day 3 post-infection for TRPV4 expression in the cecum and colon. Findings reveal that EGCs naturally express TRPV4, increasing its expression by TcdA and TcdB exposure. CDI significantly upregulates TRPV4 in the cecum and colon’s submucosal and myenteric plexus regions. TRPV4 mediates TNF-α release in EGCs and is partially involved in the increase in IL-6 gene expression triggered by these toxins. Our results highlight TRPV4’s role in triggering EGC apoptosis via caspase 3 activation and inhibiting the reduction of Bcl-2, an anti-apoptotic protein in EGCs caused by C. difficile toxins. These results highlight TRPV4’s significant role in CDI pathogenesis and its potential as a therapeutic target to counteract the detrimental effects of C. difficile toxins on enteric glia.https://doi.org/10.1186/s12950-024-00425-7C. difficileEnteric gliaTRPV4InflammationCell death |
| spellingShingle | Dvison de Melo Pacífico Deiziane Viana da Silva Costa Maria Lucianny Lima Barbosa Conceição Silva Martins Rebouças Simone de Goes Simonato Cirle Alcantara Warren Maria Luana Gaudencio dos Santos Morais Renata Ferreira de Carvalho Leitao Gerly Anne de Castro Brito TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B Journal of Inflammation C. difficile Enteric glia TRPV4 Inflammation Cell death |
| title | TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B |
| title_full | TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B |
| title_fullStr | TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B |
| title_full_unstemmed | TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B |
| title_short | TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B |
| title_sort | trpv4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by clostridioides difficile toxins a and b |
| topic | C. difficile Enteric glia TRPV4 Inflammation Cell death |
| url | https://doi.org/10.1186/s12950-024-00425-7 |
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