Dataset Information

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:Gram-negative bacteria are associated with a wide spectrum of infectious diseases in humans. Inflammasomes are cytosolic protein complexes that are assembled when the cell encounters pathogens or other harmful agents. The non-canonical caspase-4/5 inflammasome is activated by Gram-negative bacteria-derived lipopolysaccharide (LPS) and by endogenous oxidized phospholipids. Protein secretion is a critical component of the innate immune response. Here, we have used label-free quantitative proteomics to characterize global protein secretion in response to non-canonical inflammasome activation upon intracellular LPS recognition in human primary macrophages. Before proteomics, the total secretome was separated into two fractions, enriched extracellular vesicle (EV) fraction and rest-secretome (RS) fraction using size-exclusion centrifugation. We identified 1048 proteins from the EV fraction and 1223 proteins from the RS fraction. From these, 640 were identified from both fractions suggesting that the non-canonical inflammasome activates multiple, partly overlapping protein secretion pathways. We identified several secreted proteins that have a critical role in host response against severe Gram-negative bacterial infection. The soluble secretome (RS fraction) was highly enriched with inflammation-associated proteins upon intracellular LPS recognition. Several ribosomal proteins were highly abundant in the EV fraction upon infection, and our data strongly suggest that secretion of translational machinery and concomitant inhibition of translation are important parts of host response against Gram-negative bacteria sensing caspase-4/5 inflammasome. Intracellular recognition of LPS resulted in the secretion of two metalloproteinases, adisintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and MMP14, in the enriched EV fraction. ADAM10 release was associated with the secretion of TNF, a key inflammatory cytokine, and M-CSF, an important growth factor for myeloid cells probably through ADAM10-dependent membrane shedding of these cytokines. Caspase-4/5 inflammasome activation also resulted in secretion of danger-associated molecules S100A8 and prothymosin-α in the enriched EV fraction. Both S100A8 and prothymosin-α are ligands for toll-like receptor 4 recognizing extracellular LPS, and they may contribute to endotoxic shock during non-canonical inflammasome activation.

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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