Exploring the EPO/EPOR-βCR/TLR9 pathways in sepsis-associated encephalopathy: Therapeutic implications of EPO and HBSP

Objective: Delirium is a prominent clinical manifestation of sepsis-associated encephalopathy (SAE) and is closely linked to increased mortality and adverse outcomes. Erythropoietin (EPO), traditionally used for treating anemia, is increasingly recognized for its non-hematopoietic tissue-protective effects. However, the relationship between EPO and the development of SAE, as well as the underlying mechanisms, remain unclear.

Methods: First, a retrospective analysis of clinical data from 150 septic patients was conducted to assess the correlation between serum EPO levels and delirium incidence and 28-day mortality. Second, the effects of EPO and its derivative helix B surface peptide (HBSP) on neuroinflammation and neuroplasticity were evaluated in vivo and in vitro.

Results: Elevated serum EPO levels were identified as an independent risk factor for delirium. Animal studies demonstrated a positive correlation between elevated EPO and the severity of sepsis and SAE. Mechanistically, high-dose EPO exacerbated systemic inflammation, disrupted the blood-brain barrier, and impaired cognition in septic rats. Conversely, treatment with low-dose EPO or HBSP upregulated the expression of βCR and TLR9, inhibiting microglia M1 polarization while promoting M2 polarization, ultimately attenuating neuroinflammation and neuronal Apoptosis. However, this neuroprotective effect was abolished by βCR knockdown or TLR9 Agonist ODN1826.

Conclusion: In SAE, EPO exhibits a complex, concentration-dependent role: moderate EPO elevation can limit inflammatory cascades, while high levels may exacerbate inflammation. Mechanistically, activation of microglial EPOR-βCR inhibits the TLR9/MyD88/NF-κB signaling pathway. These findings offer new insights into the nuanced role of EPO in SAE pathogenesis.

EPO; Microglia; Neuroinflammation; TLR9; sepsis-associated encephalopathy; βCR.