Extracellular Histones in Inflammatory Responses

Extracellular histones are nuclear proteins released into the extracellular space during cell death or active processes such as the formation of neutrophil extracellular traps (NETs). Once outside the nucleus, these cationic molecules act as potent damage-associated molecular patterns (DAMPs), engaging pattern recognition receptors on immune and endothelial cells. Their interaction with Toll-like receptors and other signalling pathways induces cytotoxicity, pro-inflammatory cytokine release and coagulation activation, thereby contributing to a diverse range of inflammatory pathologies including sepsis, trauma, cardiovascular disease and autoimmune disorders. Research in the past decade has elucidated mechanisms of histone-mediated tissue injury and highlighted strategies for neutralising their harmful effects. Therapeutic approaches under evaluation include neutralising antibodies, polyanionic compounds, receptor antagonists and enzymes that degrade extracellular histones. These interventions aim to mitigate organ dysfunction, reduce thrombotic complications and improve outcomes in patients with acute and chronic inflammatory disorders.

Research from Nature Portfolio

Recent studies have shown that proteins released within NETs act directly on adaptive immune cells. One key investigation demonstrated that histones present on NETs engage Toll-like receptor 2 on naïve T cells, triggering STAT3 phosphorylation and promoting their differentiation into interleukin-17-producing Th17 cells. This finding reveals a direct mechanistic link between innate neutrophil activation and adaptive T cell responses in autoimmune and infectious contexts. By identifying histones as crucial modulators of T cell fate, this work opens avenues for targeted therapies aimed at disrupting aberrant Th17 polarization in inflammatory diseases.

Extracellular Histones in Inflammatory Responses publication trend

The graph below shows the total number of articles in extracellular histones in inflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular histones: Nuclear proteins released into the extracellular space during cell death or NET formation, acting as pro-inflammatory mediators.

Damage-associated molecular patterns (DAMPs): Endogenous molecules that signal tissue injury and trigger innate immune responses.

Neutrophil extracellular traps (NETs): Web-like structures composed of DNA and histones expelled by neutrophils to trap pathogens.

Toll-like receptor 2 (TLR2): A pattern recognition receptor on immune cells that recognises microbial and endogenous ligands, including histones.

Th17 cells: A subset of CD4+ T helper cells that produce interleukin-17 and are implicated in host defence and autoimmunity.

Mass spectrometry: An analytical technique used to quantify and characterise proteins, including circulating histones, in biological samples.

References

1. Targeting extranuclear histones to alleviate acute and chronic inflammation. Trends in Pharmacological Sciences (2024).
2. Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2. Nature Communications (2022).
3. Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes. Cell Death & Disease (2024).
4. Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients. Journal of Translational Medicine (2023).