Microglia-derived iron-overloaded exosomes induce neuronal ferroptosis and aggravate neurological impairment after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is one of the main subtypes of hemorrhagic stroke and is often accompanied by poor neurological prognosis. The residual neurological dysfunction imposes a serious burden on the patients’ family and society. Iron homeostasis imbalance is considered to be a key factor that causes cognitive dysfunction in patients with a variety of neurological diseases. Extracellular vesicles, including exosomes (EXs), are key transporters of intercellular substances and signal transduction. This study explored whether EXs are involved in iron metabolism after bleeding and if they affect disease prognosis. We first analyzed EXs derived from various cells in the nervous system after SAH and found that the iron ion content in EXs from microglia (MC-EXs) is significantly increased and causes damage to neuronal cell activity. Next, after uncovering the uptake mechanism of MC-EXs in neurons, we combined transcriptomic analysis and SAH in in vivo and in vitro models. We found that MC-EXs induced the occurrence of neuronal ferroptosis by transducing iron ions, and aggravated motor, sensory and cognitive impairments in SAH mice. We also screened and verified the C3/C5/NF-κB pathway in neurons and found that this is the main molecular mechanism underlying the damage caused by iron-overloaded MC-EXs. This research provides important evidence for the role of extracellular vesicles in the progression of SAH and provides direction for new treatment options in the future.