Activated Protein C blocks the inhibitory effect on neurite outgrowth by extracellular histones that mediates its inhibition through a retrograde YB-1 signal

Axonal regeneration in the mature CNS is limited by inhibitory factors within the extracellular environment. In this study, we show that histones H3 and H4 inhibit neurite outgrowth when applied to cortical neurons in vitro, and that this effect can be reversed by the addition of activated protein C (APC). Elevated levels of histones H3 and H4 were also detected in cerebrospinal fluid following CNS injury, and treatment with APC significantly increased axonal regeneration. Mechanistically, we have determined that histones activate a retrograde signaling cascade that results in phosphorylation of the transcription factor YB-1, and that neurite outgrowth is impaired when YB-1 is overexpressed in cortical neurons. These findings identify extracellular histones as a new class of growth-inhibiting molecules within the injured CNS.