Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle

Abstract

Inflammation is the ultimate response to the constant challenges of the immune system by microbes, irritants or injury. The inflammatory cascade initiates with the recognition of microorganism-derived pathogen associated molecular patterns (PAMPs) and host cell-derived damage associated molecular patterns (DAMPs) by the pattern recognition receptors (PRRs). DNA as a molecular PAMP or DAMP is sensed directly or via specific binding proteins to instigate proinflammatory response. Some of these DNA binding proteins also participate in canonical DNA repair pathways and recognise damaged DNA to initiate DNA damage response. In this review we aim to capture the essence of the complex interplay between DNA damage response and the proinflammatory signalling through representative examples. Aetiology and molecular consequences of inflammationInflammation, from the latin inflammare: set on fire, in mammals is the natural defence mechanism of the immune system in response to the constant challenges it is exposed to including injury, toxins and microorganisms, low level cosmic or medical quality radiations (X-ray, -irradiation or UVA/B), drugs and air pollutants (e.g. asbestos or cigarette smoke) 1,2 *. Inflammation is a hallmark of aging and many chronic diseases such as obesity, Chron's disease, Parkinson's disease and autoimmune diseases just to name a few [3][4][5][6][7] . *Additional on-line references are marked by superscript numbers 3The first phase of a complex defence mechanism is acute inflammation instigated by the infiltrated peripheral polymorphonuclear leukocytes (neutrophils), granulocytes (eosinophils) and tissue resident phagocytes (macrophages) at the site of insult. The pro-inflammatory signal is transmitted through the PRRs that can identify danger through DAMPs (e.g. ROS, circulating DNA fragments), cytokines or chemokines released by the damaged tissue or PAMPs from pathogens [1] 8 . The initial role of these cells is to remove the invading pathogen and initiate tissue repair 9 .One of the major defence mechanisms of the activated neutrophils and macrophages is the production of a vast spectrum of endogenous reactive oxygen (ROS) and nitrogen (RNS) species 10 in a process termed "respiratory burst" 11 (see below). However, ROS, as well as the more stable and less reactive by-product of ROS production, hydrogen-peroxide (H 2 O 2 ), are more than toxic products of respiratory burst, they are also effectors for a plethora of signalling pathways inducing innate and adaptive immune cell recruitment, proliferation, tissue healing, cell survival or apoptosis [12][13][14] . Generation of inflammation-induced ROS and RNS mtDNA damageThe circular mtDNA constitutes 1% of total cellular DNA, is of symbiotic bacterial origin, and compared to nuDNA has a very different molecular organisation and regulation. mtDNA has no histones and the methylation of CpG repeat motifs is under-represented, therefore it is particularly vulnerable to damage by endogenous ROS generated by the oxidative electron transpor...

Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging

“…Persistent DNA damage, including oxidative damage, is well known to stimulate the production of inflammatory mediators (Chatzinikolaou et al, 2014;Palmai-Pallag and Bachrati, 2014), a dynamic that is exacerbated by DNA repair deficiency (Karakasilioti et al, 2013). Furthermore, Yanagi and co-workers have reported that ubiquitinated FANCD2 inhibits NF-κB transcriptional activity and suppresses transcription of the TNF-α gene (Matsushita et al, 2011).…”

“…Consequently, FA patients at an early age phenocopy the inflammaging of normal aging, suggesting that FA should be characterized as a premature inflammaging disorder, from which flow the pathologies that overlap with those of normal aging (see above) ( Figure 1 ). Since DNA damage can induce inflammation and inflammation can provoke DNA damage (Palmai-Pallag and Bachrati, 2014), FA patients are trapped in a downward spiral.…”

A perspective on NETosis in diabetes and cardiometabolic disorders

“…For instance, extracellular histones, in addition to being bactericidal, can also kill eukaryotic cells and induce tissue toxicity and thrombosis [16e18]. Circulating cell free double strand DNA is recognized as a "danger-associated molecular pattern" (DAMP) and can induce an exaggerated activation of innate immunity, whereby inflammation-induced DNA damage and DNA-induced inflammation form a vicious cycle [19]. As a result, NETosis and NET-associated components can induce tissue damage.…”

Diet-induced vitamin D deficiency triggers inflammation and DNA damage profile in murine myometrium

“…This can promote genomic instability characterized by defects in DNA repair and accumulation of DNA damage 30,31. To test whether vitamin D deficiency initiates DNA damage in myometrial tissues, we performed immunohistochemical analyses using immunoreactive γH2AX (a DNA damage marker) via polyclonal anti-γH2AX antibodies (Figure 6A).…”