DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity

Immunity. 2015 Feb 17;42(2):332-343. doi: 10.1016/j.immuni.2015.01.012.

Abstract

Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia / immunology*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Bone Marrow Cells / immunology
  • Cell Line
  • Cytosol / immunology
  • Cytosol / microbiology
  • DNA / immunology*
  • DNA Damage*
  • DNA Repair / genetics
  • Enzyme Activation / immunology
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon-alpha / biosynthesis
  • Interferon-beta / biosynthesis
  • Interferon-gamma / biosynthesis
  • Listeria monocytogenes / immunology*
  • Listeriosis / immunology*
  • Macrophages / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Interferon-alpha
  • MPYS protein, mouse
  • Membrane Proteins
  • RNA, Small Interfering
  • Interferon-beta
  • Interferon-gamma
  • DNA
  • Tbk1 protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases