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A Dectin-1-Caspase-8 Pathway Licenses Canonical Caspase-1 Inflammasome Activation and Interleukin-1? Release in Response to a Pathogenic Fungus.

ABSTRACT: Background:Paracoccidioides brasiliensis is equipped with an arsenal of virulence factors that are crucial for causing infection. Our group previously defined the NLRP3 inflammasome as a mediator of P brasiliensis-induced cell damage recognition and induction of effective Th1 immune responses. However, deficiency of caspase-1 only partially reduced interleukin (IL)-1? levels. Methods:In this study, using chemical inhibitors as well as genetically modified mice, we identify an additional pathway for IL-1? production in response to P brasiliensis infection. Results:Paracoccidioides brasiliensis initiated caspase-8-mediated IL-1? production, an event that was necessary for transcriptional priming and posttranslational processing of pro-IL-1?. Caspase-8 synergizes with the canonical NLRP3 inflammasome pathway to control caspase-1 processing and IL-1? maturation, providing a regulatory role for caspase-8 in host resistance to in vivo P brasiliensis infection. Conclusions:Taken together, these findings revealed an important role for caspase-8 in the innate immune response of host cells to P brasiliensis infection, demonstrating a connected network between noncanonical and canonical inflammasomes to coordinate IL-1? production during fungal challenge.

SUBMITTER: Ketelut-Carneiro N

PROVIDER: S-EPMC6279136 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A Dectin-1-Caspase-8 Pathway Licenses Canonical Caspase-1 Inflammasome Activation and Interleukin-1β Release in Response to a Pathogenic Fungus.

Ketelut-Carneiro Natália N Ghosh Sreya S Levitz Stuart M SM Fitzgerald Katherine A KA da Silva João Santana JS

The Journal of infectious diseases 20180101 2

<h4>Background</h4>Paracoccidioides brasiliensis is equipped with an arsenal of virulence factors that are crucial for causing infection. Our group previously defined the NLRP3 inflammasome as a mediator of P brasiliensis-induced cell damage recognition and induction of effective Th1 immune responses. However, deficiency of caspase-1 only partially reduced interleukin (IL)-1β levels.<h4>Methods</h4>In this study, using chemical inhibitors as well as genetically modified mice, we identify an addi ...[more]

PMID: 29099934

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Project description:AIMS:The involvement of pyroptosis in ischemic stroke remains to be established. Therefore, we used the specific pyroptosis inhibitor Vx765 as an experimental intervention target in a murine model of stroke. METHODS:A total of 564 C57BL/6 mice were subjected to photothrombotic procedures and treated via gavage with Vx765 at 1-hour post-ischemia. We subsequently assessed the expression of Gasdermin D (GSDMD), inflammasomes, caspase-1, and interleukin-1? (IL-1?) using immunofluorescence (IF) and Western blot (WB) analyses. We also examined ultrastructural changes of cortical neurons with transmission electron microscopy (TEM) and measured infarct volumes dynamically by magnetic resonance imaging (MRI). Moreover, we evaluated the neurologic deficits by modified neurological severity scores, the rotarod test, and Treadscan. RESULTS:Elevated expression of GSDMD and GSDMD p30, the pore-forming subunit, was evident in the peri-ischemic region on days one and three post-ischemia. The neuronal plasma, nuclear, and mitochondrial membranes showed ultrastructural damage at day three post-stroke. Elevated expression of inflammasomes, caspase-1, and IL-1? was also present on days one and three post-injury. There were significant differences between Vx765-treated and vehicle groups in mean infarct volumes (14.36 vs 21.52 mm3 ; 12.34 vs 18.56 mm3 ; 4.13 vs 10.06 mm3 ; P < .05 at day one, three, and seven post-surgery, respectively). Mice treated with Vx765 showed better motor recovery as assessed by serial behavior tests and had better neuronal survival, which was attributable to pyroptosis inhibition, as illustrated by downregulated expression of the effector protein GSDMD, inflammasomes, caspase-1, and IL-1?. Besides, treatment with Vx765 preserved neuronal membrane structures after the ischemic injury. CONCLUSIONS:Pyroptosis emerges as an important pathway for neuronal death in an acute ischemic stroke. Vx765, a low molecular weight drug that has proven safe in clinical epilepsy trials, has potential therapeutic value for cerebral ischemia by targeting the canonical inflammasome pathway of pyroptosis.

Dataset Information

A Dectin-1-Caspase-8 Pathway Licenses Canonical Caspase-1 Inflammasome Activation and Interleukin-1? Release in Response to a Pathogenic Fungus.

Publications

A Dectin-1-Caspase-8 Pathway Licenses Canonical Caspase-1 Inflammasome Activation and Interleukin-1β Release in Response to a Pathogenic Fungus.

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