CXCL8 delivered by plasma-derived exosomes induces the symptoms of post-traumatic stress disorder through facilitating astrocyte-neuron communication.

Extracellular vesicles (EVs) play an important role in post-traumatic stress disorder (PTSD). This study is aimed to investigate the possible molecular mechanism of CD63 mediating CXCL8 delivery via EVs to affect astrocyte-neuron communication in PTSD. The neuron-derived EVs (NDEVs) and astrocyte-derived EVs (ADEVs) were isolated from plasma in PTSD patients. Next, the uptake of EVs by neurons was assessed. Following determination of the interaction between CD63 and CXCL8, gain- and loss-of-function experiments were performed in astrocytes. Finally, a PTSD mouse model was established using the single prolonged stress and electric foot shock to confirm the effects of plasma-derived EVs delivering CXCL8 on anxiety- and depression-like behaviors in PTSD mice. EVs derived from plasma of PTSD patients aggravated anxiety- and depression-like behaviors in PTSD mice. CXCL8 was a key gene upregulated in both NDEVs and ADEVs from plasma of PTSD patients, which could be delivered into EVs by CD63. Meanwhile, CXCL8 was also highly expressed in plasma-derived EVs. In vivo experiments also verified that plasma-derived EVs could enhance astrocyte-neuron communication by delivering CXCL8, and silencing of CXCL8 ameliorated anxiety- and depression-like behaviors in PTSD mice. Taken together, CD63 promotes delivery of CXCL8 via EVs to induce PTSD by enhancing astrocyte-neuron communication, suggesting the potential of CD63 mediating delivery of CXCL8 via EVs as a therapeutic target for PTSD.