ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages.
Sci Rep
; 8(1): 3788, 2018 02 28.
Article
em En
| MEDLINE
| ID: mdl-29491424
ABSTRACT
The NLRC4 inflammasome recognizes bacterial flagellin and components of the type III secretion apparatus. NLRC4 stimulation leads to caspase-1 activation followed by a rapid lytic cell death known as pyroptosis. NLRC4 is linked to pathogen-free auto-inflammatory diseases, suggesting a role for NLRC4 in sterile inflammation. Here, we show that NLRC4 activates an alternative cell death program morphologically similar to apoptosis in caspase-1-deficient BMDMs. By performing an unbiased genome-wide CRISPR/Cas9 screen with subsequent validation studies in gene-targeted mice, we highlight a critical role for caspase-8 and ASC adaptor in an alternative apoptotic pathway downstream of NLRC4. Furthermore, caspase-1 catalytically dead knock-in (Casp1 C284A KI) BMDMs genetically segregate pyroptosis and apoptosis, and confirm that caspase-1 does not functionally compete with ASC for NLRC4 interactions. We show that NLRC4/caspase-8-mediated apoptotic cells eventually undergo plasma cell membrane damage in vitro, suggesting that this pathway can lead to secondary necrosis. Unexpectedly, we found that DFNA5/GSDME, a member of the pore-forming gasdermin family, is dispensable for the secondary necrosis that follows NLRC4-mediated apoptosis in macrophages. Together, our data confirm the existence of an alternative caspase-8 activation pathway diverging from the NLRC4 inflammasome in primary macrophages.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao Cálcio
/
Apoptose
/
Caspase 1
/
Proteínas Reguladoras de Apoptose
/
Caspase 8
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Proteínas Adaptadoras de Sinalização CARD
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Inflamassomos
/
Macrófagos
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos