Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity

PLoS Pathog. 2017 Dec 18;13(12):e1006785. doi: 10.1371/journal.ppat.1006785. eCollection 2017 Dec.

Abstract

Bacterial pathogens that compromise phagosomal membranes stimulate inflammasome assembly in the cytosol, but the molecular mechanisms by which membrane dynamics regulate inflammasome activity are poorly characterized. We show that in murine dendritic cells (DCs), the endosomal adaptor protein AP-3 -which optimizes toll-like receptor signaling from phagosomes-sustains inflammasome activation by particulate stimuli. AP-3 independently regulates inflammasome positioning and autophagy induction, together resulting in delayed inflammasome inactivation by autophagy in response to Salmonella Typhimurium (STm) and other particulate stimuli specifically in DCs. AP-3-deficient DCs, but not macrophages, hyposecrete IL-1β and IL-18 in response to particulate stimuli in vitro, but caspase-1 and IL-1β levels are restored by silencing autophagy. Concomitantly, AP-3-deficient mice exhibit higher mortality and produce less IL-1β, IL-18, and IL-17 than controls upon oral STm infection. Our data identify a novel link between phagocytosis, inflammasome activity and autophagy in DCs, potentially explaining impaired antibacterial immunity in AP-3-deficient patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adaptor Protein Complex 3 / deficiency*
  • Adaptor Protein Complex 3 / genetics
  • Adaptor Protein Complex 3 / immunology
  • Animals
  • Autophagy / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology*
  • Dendritic Cells / pathology
  • Female
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-17 / biosynthesis
  • Interleukin-18 / biosynthesis
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Proteins / genetics
  • NLR Proteins / immunology
  • Phagocytosis
  • Salmonella Infections, Animal / immunology
  • Salmonella Infections, Animal / pathology
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / pathogenicity
  • Transcriptional Activation

Substances

  • Adaptor Protein Complex 3
  • Inflammasomes
  • Interleukin-17
  • Interleukin-18
  • Interleukin-1beta
  • NLR Proteins