Research on the Regulatory Role and Mechanism of the Immune Negative Regulator TIPE2 in Cognitive Impairment Induced by Long-Term Alcohol Exposure

摘要

Objective: Alcohol use disorder(AUD) is a chronic and relapsing condition characterized by compulsive consumption, impaired control over intake, and the emergence of negative emotional states upon abstinence. Chronic heavy drinking induces profound alterations in brain structure and function, including widespread cortical atrophy and selective neuronal loss in critical regions such as the hippocampus, cortex, cerebellum, thalamus, and hypothalamus, along with widespread disruption of neural connectivity. As a result, approximately 50–70% of individuals diagnosed with AUD develop mild to moderate neurocognitive impairment. The pathogenesis of cognitive impairment induced by chronic alcohol consumption remains incompletely understood, and no single mechanism can fully its neurotoxic effects. Growing evidence suggests that multiple interconnected pathways are involved, among which inflammation and disrupted synaptic plasticity are particularly prominent. Studies have shown that ethanol exposure alters levels of inflammatory cytokines-including TNF-α, IL-1β, and IL-6-as well as synaptic proteins such as BDNF and PSD95 in mice. These changes are accompanied by microglial overactivation and structural alterations in synapses. Tumor necrosis factor-α(TNFα)-inducible protein 8-like 2(TIPE2) is a recently identified anti-inflammatory regulator that plays a crucial role in maintaining immune homeostasis in various autoimmune and inflammatory diseases. Acting as a negative regulator of both innate and adaptive immunity, TIPE2 attenuates signaling through the T cell receptor(TCR) and Toll-like receptor(TLR) pathways. It is highly expressed in cognitive-relevant brain regions such as the hippocampus and cerebral cortex. Emerging evidence suggests TIPE2 as a promising therapeutic target for ameliorating cognitive impairment. Based on this rationale, the present study aims to investigate the role of TIPE2 in alcohol use disorder–induced neuroinflammation and associated cognitive deficits. Methods: The mice were divided into four groups:(1) control group;(2) EtOH group(20% w/v, 3 months);(3) EtOH + TIPE2-NC group;(4) EtOH + TIPE2-OE group. After two months of ethanol consumption, a subset of mice received bilateral intrahippocampal injections of either TIPE2-overexpressing(TIPE2-OE) or negative control(TIPE2-NC) AAV vectors via stereotaxic surgery(0.8 μL per side). Following surgery, ethanol administration was continued for an additional month. Behavioral tests—including the Morris water maze(MWM), Y-maze, and novel object recognition(NOR)—were subsequently conducted to evaluate learning, memory, and spatial discrimination. Results: The results showed that Chronic alcohol-exposed mice performed significantly poorer than the control group in terms of learning ability and spatial discrimination ability, whereas the mice with TIPE2-overexpressing showed no significant difference from the control group. Western blot analysis showed that chronic alcohol exposure in mice led to a reduction in TIPE2 protein levels in the hippocampus, accompanied by a significant decrease in brain-derived neurotrophic factor(BDNF) and postsynaptic density protein 95(PSD95), along with an increase in the pro-inflammatory cytokines interleukin-1β(IL-1β) and interleukin-6(IL-6). Overexpression of TIPE2 markedly ameliorated these inflammatory responses and deficits in synaptic plasticity. Immunofluorescence staining indicated that chronic alcohol consumption induced hyperactivation of hippocampal microglia, which was attenuated following TIPE2 overexpression. Furthermore, Golgi staining demonstrated that TIPE2 overexpression significantly restored synaptic plasticity impairments in the hippocampus of alcohol-exposed mice. Conclusion: Based on these results, we conclude that TIPE2 plays a critical role in chronic alcohol–induced neuroinflammation and associated cognitive deficits; however, the precise mechanism of action remains unclear. Further studied will focus on elucidating how TIPE2 overexpression attenuates neuroinflammation and restores cognitive function following chronic alcohol exposure.

关键词

AUD / TIPE 2 / cognitive impairment / inflammation / synaptic plasticity