Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome

PLoS Pathogens

Graziele Z. Manin¹  Danielle P. A. Mascarenhas¹  Larissa D. Cunha¹  Talita D. Fernandes¹  Fernanda V. S. Castanheira¹  Dario S. Zamboni¹  Daiane M. Cerqueira¹  Marcelo S. F. Pereira¹ 

[1] Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo. Ribeirão Preto, Brazil

关键词: Macrophages;    Legionella pneumophila;    Inflammasomes;    Flagellin;    Cell death;    Pathogen motility;    DAPI staining;    Legionella;   

DOI  :  10.1371/journal.ppat.1006502

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Legionella pneumophila is a Gram-negative, flagellated bacterium that survives in phagocytes and causes Legionnaires’ disease. Upon infection of mammalian macrophages, cytosolic flagellin triggers the activation of Naip/NLRC4 inflammasome, which culminates in pyroptosis and restriction of bacterial replication. Although NLRC4 and caspase-1 participate in the same inflammasome, Nlrc4-/- mice and their macrophages are more permissive to L. pneumophila replication compared with Casp1/11-/-. This feature supports the existence of a pathway that is NLRC4-dependent and caspase-1/11-independent. Here, we demonstrate that caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in response to flagellin-positive bacteria. Accordingly, caspase-8 is activated in Casp1/11-/- macrophages in a process dependent on flagellin, Naip5, NLRC4 and ASC. Silencing caspase-8 in Casp1/11-/- cells culminated in macrophages that were as susceptible as Nlrc4-/- for the restriction of L. pneumophila replication. Accordingly, macrophages and mice deficient in Asc/Casp1/11-/- were more susceptible than Casp1/11-/- and as susceptible as Nlrc4-/- for the restriction of infection. Mechanistically, we found that caspase-8 activation triggers gasdermin-D-independent pore formation and cell death. Interestingly, caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in wild-type macrophages, but it is only activated when caspase-1 or gasdermin-D is inhibited. Our data suggest that caspase-8 activation in the Naip5/NLRC4/ASC inflammasome enable induction of cell death when caspase-1 or gasdermin-D is suppressed.

【 授权许可】

CC BY