Abstract
The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection.
Highlights
The rapid response to infections or tissue injury is one of the main features of the innate immune system
Little is known about their functions as damage-associated molecular pattern molecules
Our study shows for the first time that extracellular histones trigger the induction of chemotactic chemokines from monocytes
Summary
The rapid response to infections or tissue injury is one of the main features of the innate immune system. To this end pattern recognition receptors (PRRs) play an important role in these processes. Histones are ubiquitous proteins that are mainly involved in organizing DNA into nucleosomes and chromatin They normally have only an intracellular function and are not actively released into the extracellular environment. During inflammatory and/or necrotic conditions histones can be mobilized from stressed, damaged, or dying cells Such complications are for instance seen in patients with malignant tumors, trauma associated lung injuries, malaria, or severe infectious diseases [7,8,9,10]
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