The colonic pathogen Entamoeba histolytica activates caspase-4/1 that cleaves the pore-forming protein gasdermin D to regulate IL-1ß secretion.
PLoS Pathog
; 18(3): e1010415, 2022 03.
Article
in En
| MEDLINE
| ID: mdl-35303042
ABSTRACT
A hallmark of Entamoeba histolytica (Eh) invasion in the gut is acute inflammation dominated by the secretion of pro-inflammatory cytokines TNF-α and IL-1ß. This is initiated when Eh in contact with macrophages in the lamina propria activates caspase-1 by recruiting the NLRP3 inflammasome complex in a Gal-lectin and EhCP-A5-dependent manner resulting in the maturation and secretion of IL-1ß and IL-18. Here, we interrogated the requirements and mechanisms for Eh-induced caspase-4/1 activation in the cleavage of gasdermin D (GSDMD) to regulate bioactive IL-1ß release in the absence of cell death in human macrophages. Unlike caspase-1, caspase-4 activation occurred as early as 10 min that was dependent on Eh Gal-lectin and EhCP-A5 binding to macrophages. By utilizing CRISPR-Cas9 gene edited CASP4/1, NLRP3 KO and ASC-def cells, caspase-4 activation was found to be independent of the canonical NLRP3 inflammasomes. In CRISPR-Cas9 gene edited CASP1 macrophages, caspase-4 activation was significantly up regulated that enhanced the enzymatic cleavage of GSDMD at the same cleavage site as caspase-1 to induce GSDMD pore formation and sustained bioactive IL-1ß secretion. Eh-induced IL-1ß secretion was independent of pyroptosis as revealed by pharmacological blockade of GSDMD pore formation and in CRISPR-Cas9 gene edited GSDMD KO macrophages. This was in marked contrast to the potent positive control, lipopolysaccharide + Nigericin that induced high expression of predominantly caspase-1 that efficiently cleaved GSDMD with high IL-1ß secretion/release associated with massive cell pyroptosis. These results reveal that Eh triggered "hyperactivated macrophages" allowed caspase-4 dependent cleavage of GSDMD and IL-1ß secretion to occur in the absence of pyroptosis that may play an important role in disease pathogenesis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Entamoeba histolytica
Limits:
Humans
Language:
En
Journal:
PLoS Pathog
Year:
2022
Document type:
Article
Affiliation country:
Canadá