Cytolethal distending toxin-induced release of interleukin-1ß by human macrophages is dependent upon activation of glycogen synthase kinase 3ß, spleen tyrosine kinase (Syk) and the noncanonical inflammasome.
Cell Microbiol
; 22(7): e13194, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-32068949
ABSTRACT
Cytolethal distending toxins (Cdt) are a family of toxins produced by several human pathogens which infect mucocutaneous tissue and induce inflammatory disease. We have previously demonstrated that the Aggregatibacter actinomycetemcomitans Cdt induces a pro-inflammatory response from human macrophages which involves activation of the NLRP3 inflammasome. We now demonstrate that in addition to activating caspase-1 (canonical inflammasome), Cdt treatment leads to caspase-4 activation and involvement of the noncanonical inflammasome. Cdt-treated cells exhibit pyroptosis characterised by cleavage of gasdermin-D (GSDMD), release of HMGB1 at 24 hr and LDH at 48 hr. Inhibition of either the canonical (caspase-1) or noncanonical (caspase-4) inflammasome blocks both Cdt-induced release of IL-1ß and induction of pyroptosis. Analysis of upstream events indicates that Cdt induces Syk phosphorylation (activation); furthermore, blockade of Syk expression and inhibition of pSyk activity inhibit both Cdt-induced cytokine release and pyroptosis. Finally, we demonstrate that increases in pSyk are dependent upon Cdt-induced activation of GSK3ß. These studies advance our understanding of Cdt function and provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as A. actinomycetemcomitans.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Toxinas Bacterianas
/
Interleucina-1beta
/
Inflamasomas
/
Glucógeno Sintasa Quinasa 3 beta
/
Quinasa Syk
/
Macrófagos
Límite:
Humans
Idioma:
En
Revista:
Cell Microbiol
Asunto de la revista:
MICROBIOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos