Extracellular histone induces plasma hyaluronan-binding protein (factor VII activating protease) activation in vivo

► PHBP (FSAP) is a serine protease circulating as a single-chain proenzyme (pro-PHBP). ► Extracellular histones, released under hyperinflammation, mediate toxic effects. ► We find that histones potently promote the activation pro-PHBP via formation of autoactivation complex. ► Pro-PHBP activation in plasma affords bradykinin and PHBP-α2-antiplasmin complex. ► Pro-PHBP activation is observed in a sepsis model, suggesting pathophysiological role.