Clostridioides difficile toxin B alone and with pro-inflammatory cytokines induces apoptosis in enteric glial cells by activating three different signalling pathways mediated by caspases, calpains and cathepsin B.
Apoptosis
/ physiology
Bacterial Toxins
/ metabolism
Calpain
/ metabolism
Caspase 3
/ metabolism
Caspase 7
/ metabolism
Caspases
/ metabolism
Cathepsin B
/ metabolism
Clostridioides difficile
Clostridium Infections
Cytokines
/ metabolism
Humans
Neuroglia
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Signal Transduction
Tumor Necrosis Factor-alpha
/ metabolism
Apoptosis
C. difficile toxin B (TcdB)
Calpains
Caspases
Cathepsin B
Cell cycle
Cell death
Clostridioides difficile
Cysteine proteases
Enteric glial cells (EGCs)
Interferon gamma (IFN-γ)
Tumour necrosis factor alpha (TNF-α)
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
22 Jul 2022
22 Jul 2022
Historique:
received:
23
08
2021
accepted:
29
06
2022
revised:
22
06
2022
entrez:
21
7
2022
pubmed:
22
7
2022
medline:
26
7
2022
Statut:
epublish
Résumé
Clostridioides difficile infection (CDI) causes nosocomial/antibiotic-associated gastrointestinal diseases with dramatically increasing global incidence and mortality rates. The main C. difficile virulence factors, toxins A and B (TcdA/TcdB), cause cytopathic/cytotoxic effects and inflammation. We demonstrated that TcdB induces caspase-dependent, mitochondria-independent enteric glial cell (EGC) apoptosis that is enhanced by the pro-inflammatory cytokines TNF-α and IFN-γ (CKs) by increasing caspase-3/7/9 and PARP activation. Because this cytotoxic synergism is important for CDI pathogenesis, we investigated the apoptotic pathways involved in TcdB- and TcdB + CK-induced apoptosis indepth. EGCs were pre-treated with the inhibitors BAF or Q-VD-OPh (pan-caspase), Z-DEVD-fmk (caspase-3/7), Z-IETD-fmk (caspase-8), PD150606 (calpains), and CA-074Me (cathepsin B) 1 h before TcdB exposure, while CKs were given 1.5 h after TcdB exposure, and assays were performed at 24 h. TcdB and TcdB + CKs induced apoptosis through three signalling pathways activated by calpains, caspases and cathepsins, which all are involved both in induction and execution apoptotic signalling under both conditions but to different degrees in TcdB and TcdB + CKs especially as regards to signal transduction mediated by these proteases towards downstream effects (apoptosis). Calpain activation by Ca
Identifiants
pubmed: 35864342
doi: 10.1007/s00018-022-04459-z
pii: 10.1007/s00018-022-04459-z
pmc: PMC9304068
doi:
Substances chimiques
Bacterial Toxins
0
Cytokines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Tumor Necrosis Factor-alpha
0
Calpain
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Caspase 7
EC 3.4.22.-
Caspases
EC 3.4.22.-
Cathepsin B
EC 3.4.22.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
442Informations de copyright
© 2022. The Author(s).
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