Red Blood Cell-Derived Exosomes Deliver Complement C5 to Exacerbate Neuroinflammation and Neuronal Injury after Intracerebral Hemorrhage

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Intracerebral hemorrhage (ICH) induces neuroinflammation and neuronal damage, partially driven by microglial necroptosis and M1 polarization. Recent evidence implicates red blood cell-derived exosomes (RBC-Exos) in inflammatory pathologies, yet their role in ICH remains unexplored. This study investigates how hemorrhagic RBC-Exos (ICH-Exos) regulate microglial dysfunction and neuropathology through complement signaling. RBC-Exos were isolated and validated using flow cytometry (AnnexinV+CD235+), transmission electron microscopy, nanoparticle tracking analysis, and western blot (CD63/TSG101). In vitro, hemin-treated microglia were exposed to Normal-Exos or ICH-Exos. Murine ICH models assessed neuropathology via histology (H&E, Nissl staining), adhesion molecule expression (ICAM-1/VCAM-1), and neurobehavioral tests. Proteomics identified exosomal protein cargo, complemented by C5 monoclonal antibody (mAb) blocking experiments to dissect mechanistic pathways. ICH-Exos exacerbated hemin-induced microglial necroptosis, marked by upregulated phosphorylated RIPK1, RIPK3, and MLKL, and amplified M1 polarization (elevated CD86, iNOS, CCL2; suppressed CD163, ARG1). In ICH mice, ICH-Exos aggravated cerebral hemorrhage, neuronal loss, and neurobehavioral deficits while elevating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Proteomics revealed C5 enrichment in ICH-Exos, correlating with

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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