title: Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes.
abstract: Listeria monocytogenes invades the cytoplasm of macrophages and induces the activation of caspase-1 and the subsequent maturation of IL-1beta and IL-18. Although apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC), an adaptor protein of nucleotide-binding oligomerization domain (Nod)-like receptors, has been shown to play an essential role in inducing this cellular response to L. monocytogenes, the mechanism has not been fully elucidated. In this study, we demonstrate the role of absent in melanoma 2 (AIM2), a recently described receptor of cytosolic DNA, in the activation of caspase-1 upon infection with L. monocytogenes. Secretion of IL-1beta and IL-18 from Nod-like receptor family, pyrin domain containing 3 (NLRP3) and Nod-like receptor family, caspase-activating and recruitment domain containing 4 (NLRC4) knockout macrophages in response to L. monocytogenes was only slightly decreased compared with the levels secreted from wild-type macrophages, whereas secretion from ASC knockout macrophages was completely impaired, suggesting that receptors other than NLRP3 and NLRC4 also take part in inflammasome activation in an ASC-dependent manner. To identify such receptors, the abilities of several receptor candidates (NLRP2, NLRP6, NLRP12, and AIM2) to induce the secretion of IL-1beta in response to L. monocytogenes were compared using the inflammasome system reconstructed in HEK293 cells. Among these receptor candidates, AIM2 conferred the highest responsiveness to the bacterium on HEK293 cells. Knockdown of AIM2 significantly decreased the secretion of IL-1beta and IL-18 from L. monocytogenes-infected macrophages. These results suggest that AIM2, in cooperation with NLRP3 and NLRC4, plays an important role in the activation of caspase-1 during L. monocytogenes infection.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. tsuchiya@mb.med.kyoto-u.ac.jp
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
authors.forename: Takamasa
authors.initials: T
authors.lastname: Nomura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Sylvia
authors.initials: S
authors.lastname: Daim
authors.forename: Sita R
authors.initials: SR
authors.lastname: Dewamitta
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005260:Female; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D020170:Caspase 1