Chronic ethanol exposure induces hippocampal neuroinflammation and neuronal damage via the astrocytic RUNX1/TOLLIP/TLR3 pathway

Chronic ethanol exposure (CEE) is acknowledged as a significant risk element for cognitive decline and depression, with NLRP3-related neuroinflammation identified as a crucial mechanism driving depression-like behaviors and cognitive impairment induced by CEE. Here, TLR3 is identified as a priming signal that activates NLRP3 inflammasome triggered by CEE via NF-κB p65 nuclear translocation in astrocytes. CEE-induced neuroinflammation, depressive-like behavior and cognitive impairment are alleviated by downregulation of TLR3. Mechanistically, TOLLIP, a negative regulator of TLR3 pathway, is a target gene of RUNX1, a critical transcription factor associated with inflammation. Therefore, CEE triggers NLRP3-related neuroinflammation, cognitive impairment and depressive-like behavior via RUNX1/TOLLIP/TLR3/p65 axis. Neuronal damage serves as the pathological foundation for mental disorders and is closely associated with neuroinflammatory processes. Most TLR3 in the brain is expressed in the astrocytes. Neuronal damage induced by ethanol exposure is alleviated when inflammatory reactions of astrocytes are suppressed by the inhibition of TLR3 pathway. Thus, the study offers significant insights into CEE-induced neuroinflammation and neuronal damage, as well as the relationship between these two phenomena, and offers potential therapeutic strategies.