title: CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages.
abstract: Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)-infected patients. However, the source of endogenous pyrogen (eg, IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mϕ and M-Mϕ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mϕ (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-Mϕ (resting macrophage) did not produce IL-1β and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-Mϕ and M-Mϕ to DV infection. Moreover, up-regulation of pro-IL-1β, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mϕ, whereas blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever and Japanese encephalitis virus infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mϕ. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mϕ plays a more important role than M-Mϕ in the pathogenesis of DV infection.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.forename: Szu-Ting
authors.initials: ST
authors.lastname: Chen
authors.forename: An-Hang
authors.initials: AH
authors.lastname: Yang
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Nien-Jung
authors.initials: NJ
authors.lastname: Chen
authors.forename: I-Shuen
authors.initials: IS
authors.lastname: Tsai
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
mesh_terms: D017209:Apoptosis; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000276:immunology; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003715:Dengue / Q000235:genetics / Q000276:immunology*; D003716:Dengue Virus / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D005334:Fever / Q000209:etiology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000145:classification / Q000187:drug effects / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication
chemical_list: C509771:CLEC5A protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor