Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity

Nat Commun. 2015 Jan 22;6:5779. doi: 10.1038/ncomms6779.

Abstract

Immune responses must be well restrained in a steady state to avoid excessive inflammation. However, such restraints are quickly removed to exert antimicrobial responses. Here we report a role of autophagy in an early host antifungal response by enhancing NFκB activity through A20 sequestration. Enhancement of NFκB activation is achieved by autophagic depletion of A20, an NFκB inhibitor, in F4/80(hi) macrophages in the spleen, peritoneum and kidney. We show that p62, an autophagic adaptor protein, captures A20 to sequester it in the autophagosome. This allows the macrophages to release chemokines to recruit neutrophils. Indeed, mice lacking autophagy in myeloid cells show higher susceptibility to Candida albicans infection due to impairment in neutrophil recruitment. Thus, at least in the specific aforementioned tissues, autophagy appears to break A20-dependent suppression in F4/80(hi) macrophages, which express abundant A20 and contribute to the initiation of efficient innate immune responses.

Publication types

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

MeSH terms

  • Animals
  • Autophagy*
  • Autophagy-Related Protein 7
  • Candida albicans / metabolism
  • Candidiasis / immunology*
  • Candidiasis / metabolism
  • Chemokine CXCL1 / metabolism
  • Chemokine CXCL2 / metabolism
  • Chemokines / metabolism
  • Chemotaxis
  • Cysteine Endopeptidases / metabolism*
  • Down-Regulation
  • Female
  • Immunity, Innate
  • Inflammation
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kidney / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / metabolism*
  • Myeloid Cells / metabolism
  • NF-kappa B p50 Subunit / metabolism*
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Peritoneum / metabolism
  • Signal Transduction
  • Spleen / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Atg7 protein, mouse
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Chemokines
  • Cxcl1 protein, mouse
  • Cxcl2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B p50 Subunit
  • Nfkb1 protein, mouse
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse
  • Autophagy-Related Protein 7