Neurofilament Light Chain (NF‐L) Stimulates Lipid Peroxidation to Neuronal Membrane through Microglia‐Derived Ferritin Heavy Chain (FTH) Secretion

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A part of the axonal cytoskeleton protein complex, neurofilament light chain (NF‐L) has been suggested as a pathological hallmark in various neurological disorders, including hemorrhagic stroke, vascular dementia, and cerebral small vessel disease. Neuroaxonal debris are mainly engulfed and phagocytosed by microglia, while the effects of NF‐L on microglia have not been elucidated. Ferritin heavy chain (FTH) not only reflects the age‐related status of microglia but may also be secreted into the extracellular space. After treatment of microglia with varying concentrations of NF‐L (0‐3 μg/ml), we found robust increases in the number of secretory FTH‐containing exosomes in the medium. Induction of the FTH‐containing exosomes secreted from microglia stimulates neuronal loss and membrane lipid peroxidation, as assessed by CKK8 and C11‐Bodipy581/591, respectively. However, this oxidative stress damage was attenuated by blocking Fth1 expression. Our results suggest that NF‐L, as a biomarker of axonal injury itself, could participate in neuronal ferroptosis in a nonclassical manner by secreting FTH‐containing exosomes from microglia into the extracellular matrix.

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