Citrullinated histone H2A and histone H4 on extracellular traps (CitH2A/H4-ETs)

Citrullinated histones H2A and H4 are post-translationally modified proteins that serve as structural and functional components of extracellular traps (ETs) released by neutrophils (NETs) and eosinophils (EETs) [PMID: 19897725]. The citrullination process, catalyzed by the enzyme peptidylarginine deiminase 4 (PAD4), involves the conversion of arginine residues to citrulline, which reduces the positive charge of histones and promotes massive chromatin decondensation [PMID: 23945210]. While these traps are essential for the innate immune system to capture and kill pathogens, the persistence of extracellular citrullinated histones can drive significant pathology. They act as damage-associated molecular patterns (DAMPs) that trigger further inflammation and serve as autoantigens in autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus [PMID: 25043083, PMID: 22403202]. Furthermore, these modified histones are implicated in promoting a pro-thrombotic environment and facilitating cancer metastasis [PMID: 23831269]. Therapeutic strategies focus on inhibiting PAD4 to prevent the formation of these traps or using agents like DNase and heparin to degrade the trap scaffold and neutralize histone-mediated toxicity [PMID: 27170055].

Other names

Citrullinated H2ACitrullinated H4NET-associated citrullinated histonesEET-associated citrullinated histonesExtracellular citrullinated histonesHypercitrullinated histones

Inhibition of peptidylarginine deiminase 4 (PAD4) to prevent histone citrullination and subsequent extracellular trap release, or enzymatic degradation of the DNA scaffold to neutralize the associated cytotoxic histones.