DNA damage in protective and adverse inflammatory responses: Friend of foe?
Introduction
For many years DNA damage was seen and studied from the angle of its cell autonomous effects such as activation of DNA damage responses (DDR), DNA repair, cell cycle arrest and apoptosis (in cases of insufficient repair or excessive damage levels). During the past decade however non-cell-autonomous outcomes of DNA damage have become increasingly clear. It was found that cells with affected genomes do send systemic signals shaping the physiology of the entire organism. One variety of such signals are innate immune signals. Intriguingly depending on the context and duration of genotoxic stress, related innate immune activity may have positive or negative systemic effects. This review will summarize our current knowledge of protective and detrimental inflammatory responses induced by DNA damage and discuss the impact of these responses on aging and disease.
Section snippets
The many links between DNA damage and immune response: from aging to sunlight exposure
The evident link between occurrence of genotoxic damage and subsequent activation of immune responses is well documented and extensively described in literature. We will therefore only provide a brief account of how DNA damage is linked to inflammatory responses on distinct occasions. This outline will lay ground for understanding the protective effect of some and the harmful nature of other such responses.
First of all immune responses can be triggered by external genotoxic damage experienced
Why and how is genotoxic damage visible to the immune system?
In light of clear links between DNA damage and induction of immune response, the key question is why does the immune system respond to genotoxic stress and how does it sense such stress? For decades immune system was viewed as a complex mechanism activated by organismal contact with “non-self”: viruses, microbes or parasites invading the host cells. Initial immune response was thought to be triggered by evolutionary conserved molecular signatures indicative of pathogenic presence, the so called
Persistent DNA damage as a source of chronic inflammation: protective function gone wrong?
In the previous chapter we hypothesized that damaged DNA is seen by the immune system as one of the DAMPs eliciting danger alert and systemic protection. It was thus logical to anticipate beneficial effects of DNA damage recognition by the immune system. There are however abundant reports of detrimental outcomes of DNA damage-induced immune activity.
Chronic inflammation driven by persistent genotoxic stress is believed to be an important driver of organ decline and onset of premature aging in
Hint of protective function: systemic pro-homeostatic effects of transient DNA damage
Along with abundant data linking chronic DNA damage-induced immune responses to negative organismal effects the evidence of pro-homeostatic role of immune induction linked to transient genotoxicity is currently emerging.
It has been discovered that both endogenous and exogenous germline DNA damage promote systemic stress tolerance in the nematode Caenorhabditis elegans (Ermolaeva et al., 2013). The systemic stress tolerance was linked to DNA damage-induced immune response triggered by MPK-1/ERK
Concluding remarks
Ample evidence discussed in the current review strongly supports the pro-homeostatic role of immune responses instigated by transient DNA damage. Cross species conservation of cascades and molecules implicated in recognition of damaged host DNA by the immune system and in systemic transmission of resulting immune signals, indicate a potential conserved physiological role of DNA damage in systemic danger signaling. Many extrinsic and intrinsic genotoxic stimuli are able to cause significant
Acknowledgement
The work of TP and ME is funded by the intramural funding of the Leibniz Institute on Aging – Fritz Lipmann Institute which is supported by the Leibniz Association.
References (73)
Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle
Cell Stem Cell
(2014)Death by protein damage in irradiated cells
DNA Repair (Amst.)
(2012)An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA
Dev. Cell
(2014)Anthracyclines induce DNA damage response-mediated protection against severe sepsis
Immunity
(2013)- et al.
Innate immune sensors stimulate inflammatory and immunosuppressive responses to UVB radiation
J. Invest. Dermatol.
(2014) A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans
Mol. Cell.
(2000)- et al.
Immunity: inflammation, and cancer
Cell
(2010) DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity
Immunity
(2015)Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut
Cell
(2009)DNA damage triggers a chronic autoinflammatory response: leading to fat depletion in NER progeria
Cell Metab.
(2013)