Abstract
In inflammation, extensive cell death may occur, which results in the release of chromatin components into the extracellular environment. Individually, the purified chromatin components double stranded (ds)DNA and histones have been demonstrated, both in vitro and in vivo, to display various immunostimulatory effects, for example, histones induce cytotoxicity and proinflammatory signaling through toll-like receptor (TLR)2 and 4, while DNA induces signaling through TLR9 and intracellular nucleic acid sensing mechanisms. However, DNA and histones are organized in nucleosomes in the nucleus, and evidence suggests that nucleosomes are released as such in inflammation. The cytotoxicity and proinflammatory signaling induced by nucleosomes have not been studied as extensively as the separate effects brought about by histones and dsDNA, and there appear to be some marked differences. Remarkably, little distinction between the different forms in which histones circulate has been made throughout literature. This is partly due to the limitations of existing techniques to differentiate between histones in their free or DNA-bound form. Here we review the current understanding of immunostimulation induced by extracellular histones, dsDNA and nucleosomes, and discuss the importance of techniques that in their detection differentiate between these different chromatin components.
Highlights
Chromatin components including histones and dsDNA are important damage-associated molecular patterns (DAMPs) that induce proinflammatory signaling when released into the extracellular environment
In mice TLR9 is found in macrophages, myeloid DCs, activated T cells, plasmacytoid DCs, B cells, and neutrophils, while in humans, TLR9 expression is limited to plasmacytoid DCs, B cells, and neutrophils. This results in a radically different inflammatory response towards TLR9 agonists in mice compared with humans,[12] which complicates nuclear DAMP research in animal models. Another observation that further supports the induction of inflammation by histones was reported by Abrams et al.,[13] who found that neutrophils that were incubated with purified histones released MPO and were activated to form neutrophil extracellular traps (NETs)
In peptidylarginine deiminase-4 (PAD4)-deficient mice, which are reportedly impaired in NET formation, increased levels of circulating nucleosomes were found upon LPS-challenge, similar to the increase seen in wild-type mice, suggesting that nucleosomes are derived from other cells than NETting neutrophils.[75]
Summary
In what form do histones circulate in inflammatory disease? How do the proinflammatory functions of histones compare with those of nucleosomes? How to distinguish between free histones and nucleosomes in body fluids?. Various immunostimulatory effects including proinflammatory signaling through toll-like receptors (TLRs) and cytotoxicity are initiated when these nuclear DAMPs bind to host cells (see reviews[1,2,3]) Certain of these immunostimulatory effects appear to be dictated by the form in which extracellular chromatin molecules are present, that is, histones may either circulate freely or in complex with DNA in the form of a nucleosome. This results in a radically different inflammatory response towards TLR9 agonists in mice compared with humans,[12] which complicates nuclear DAMP research in animal models Another observation that further supports the induction of inflammation by histones was reported by Abrams et al.,[13] who found that neutrophils that were incubated with purified histones released MPO and were activated to form neutrophil extracellular traps (NETs). For an overview of the immunostimulatory actions of histones, both through TLR signaling and cytotoxicity, see Figure 1
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