title: The adaptor ASC exacerbates lethal Listeria monocytogenes infection by mediating IL-18 production in an inflammasome-dependent and -independent manner.
abstract: Listeria monocytogenes induces the formation of inflammasomes and subsequent caspase-1 activation, and the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is crucial for this response. However, the role of ASC in L. monocytogenes infection in vivo is unclear. In this study, we demonstrate that ASC has a detrimental effect on host defense against L. monocytogenes infection at a lethal dose (10(6) CFU), but not at a sublethal dose (10(3) CFU). During lethal L. monocytogenes infection, serum levels of IL-18 and IL-10 were markedly elevated in WT mice, but not in ASC KO mice. IL-18 KO mice were more resistant to lethal L. monocytogenes infection than WT mice and had lower levels of serum IL-10. Furthermore, blockade of IL-10 receptor resulted in a reduction in bacterial counts, suggesting that ASC and IL-18 might exacerbate L. monocytogenes infection through induction of IL-10. We noticed that maturation of IL-18 during lethal infection was partially independent of caspase-1, but was critically dependent on ASC. ASC was required for the elevation of serum neutrophil serine protease activity, which correlated with caspase-1-independent IL-18 maturation and IL-10 production. Collectively, these results suggest that ASC plays a detrimental role in lethal L. monocytogenes infection through IL-18 production in an inflammasome-dependent and -independent manner.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez-Cuellar
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.forename: Sylvia
authors.initials: S
authors.lastname: Daim
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Sita R
authors.initials: SR
authors.lastname: Dewamitta
authors.forename: Huixin
authors.initials: H
authors.lastname: Qu
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology; D057057:Serine Proteases / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C556062:IL10 protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; C498534:Pycard protein, mouse; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D057057:Serine Proteases
keywords: ASC; Caspase-1; IL-18; Inflammasome; Listeria monocytogenes