CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages

Blood. 2013 Jan 3;121(1):95-106. doi: 10.1182/blood-2012-05-430090. Epub 2012 Nov 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Capillary Permeability
  • Carrier Proteins / immunology
  • Caspase Inhibitors / pharmacology
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Dengue / genetics
  • Dengue / immunology*
  • Dengue Virus / physiology*
  • Endothelium, Vascular / physiology
  • Fever / etiology
  • Fever / physiopathology
  • Gene Expression Regulation / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / genetics
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / genetics
  • Lectins, C-Type / antagonists & inhibitors
  • Lectins, C-Type / physiology*
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation*
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / classification
  • Macrophages / drug effects
  • Macrophages / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / physiology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Virus Replication

Substances

  • CLEC5A protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Lectins, C-Type
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Tumor Necrosis Factor-alpha
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor