Abstract
Histones are the protein component of nucleosomes, which are the basic packing unit of chromatin. However, histones are also found in the blood, both as components of nucleosomes leaked out from dead cells, or expelled from neutrophils in the active process of NET formation. Circulating histones contribute to inflammation, and to lethality in sepsis, a hyperinflammatory condition, by interacting with specific receptors, notably toll-like receptor 4 (TLR4). Here, we show that histones are also actively released by LPS-activated macrophages in association with extracellular vesicles. Vesicle-associated histones can be recovered from the plasma of mice with sepsis. Actively released histones are on the outer surface of vesicles and can interact with TLR4. Thus, activated macrophages release histones without dying, at the same time, making their DNA more accessible and communicating to other cells that infection is present.
Highlights
Histones package DNA by forming nucleosomes, the basic unit of chromatin
We observed that the distributions of the number of localizations per clutch and clutch area were significantly different in Bone marrow-derived macrophages (BMDM) challenged or not with LPS (Figures 1C–E)
We show that a part of the circulating histones in septic mice derives from monocytes/macrophages, which release them on extracellular vesicles (EVs) without dying
Summary
Histones package DNA by forming nucleosomes, the basic unit of chromatin. Blood often contains both nucleosomes and free histones, which can be used as biomarkers of various diseases. Histones are released by neutrophils during the process of NET formation [1], whereby activated neutrophils eject their chromatin to trap pathogens and plug microvessels, preventing pathogen spreading [2]. Free histones activate toll-like receptor 4 [6] and promote the release of chemokines and cytokines by inflammatory cells [4], contributing to hyperinflammation in sepsis. Injection of free histones produces a sepsis-like condition in mice and baboons, and neutralization of histones with anti-histone antibodies or injection of activated protein C (APC), a serine protease that cleaves histones, prevents lethality in sepsis [3]
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