title: ASC controls IFN-γ levels in an IL-18-dependent manner in caspase-1-deficient mice infected with Francisella novicida.
abstract: The inflammasome is a signaling platform that is central to the innate immune responses to bacterial infections. Francisella tularensis is a bacterium replicating within the host cytosol. During F. tularensis subspecies novicida infection, AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1β and IL-18. Activation of this canonical inflammasome pathway is key to limit F. novicida infection. In this study, by comparing the immune responses of AIM2 knockout (KO), ASC(KO), and Casp1(KO) mice in response to F. novicida infection, we observed that IFN-γ levels in the serum of Casp1(KO) mice were much higher than the levels observed in AIM2(KO) and ASC(KO) mice. This difference in IFN-γ production was due to a large production of IFN-γ by NK cells in Casp1(KO) mice that was not observed in ASC(KO) mice. The deficit in IFN-γ production observed in ASC(KO) mice was not due to a reduced Dock2 expression or to an intrinsic defect of ASC(KO) NK cells. We demonstrate that in infected Casp1(KO) mice, IFN-γ production is due to an ASC-dependent caspase-1-independent pathway generating IL-18. Furthermore, we present in vitro data suggesting that the recently described AIM2/ASC/caspase-8 noncanonical pathway is responsible for the caspase-1-independent IL-18 releasing activity. To our knowledge, this study is the first in vivo evidence of an alternative pathway able to generate in a caspase-1-independent pathway bioactive IL-18 to boost the production of IFN-γ, a cytokine critical for the host antibacterial response.
authors: Centre International de Recherche en Infectiologie, Université de Lyon, Lyon 69007, France;
authors: Roberto
authors: R
authors: Pierini
authors: Magali
authors: M
authors: Perret
authors: Sophia
authors: S
authors: Djebali
authors: Carole
authors: C
authors: Juruj
authors: Marie-Cécile
authors: MC
authors: Michallet
authors: Irmgard
authors: I
authors: Förster
authors: Jacqueline
authors: J
authors: Marvel
authors: Thierry
authors: T
authors: Walzer
authors: Thomas
authors: T
authors: Henry
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005603:Francisella / Q000276:immunology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D058847:Inflammasomes; D020382:Interleukin-18; C498534:Pycard protein, mouse; D007371:Interferon-gamma; D053181:Caspase 8; D020170:Caspase 1