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

Anetta Härtlova, Saskia F Erttmann, Faizal Am Raffi, Anja M Schmalz, Ulrike Resch, Sharath Anugula, Stefan Lienenklaus, Lisa M Nilsson, Andrea Kröger, Jonas A Nilsson, Torben Ek, Siegfried Weiss, Nelson O Gekara

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)332-343
Number of pages12
JournalImmunity
Volume42
Issue number2
DOIs
Publication statusPublished - 17 Feb 2015
Externally publishedYes

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