PDF(Pubmed)
Abstract：
OBJECTIVE: Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases in alcohol drinking and alcohol-related problems that develop into compulsive use in the chronic relapsing disease, alcohol use disorder (AUD). Over the past decade, neuroimmune signaling has been discovered to contribute to alcohol-induced changes in drinking, mood, and neurodegeneration. This review presents a mechanistic hypothesis supporting high mobility group box protein 1 (HMGB1) and Toll-like receptor (TLR) signaling as key elements of alcohol-induced neuroimmune signaling across glia and neurons, which shifts gene transcription and synapses, altering neuronal networks that contribute to the development of AUD. This hypothesis may help guide further research on prevention and treatment.
METHODS: The authors used the search terms \"HMGB1 protein,\" \"alcohol,\" and \"brain\" across PubMed, Scopus, and Embase to find articles published between 1991 and 2023.
UNASSIGNED: The database search found 54 references in PubMed, 47 in Scopus, and 105 in Embase. A total of about 100 articles were included.
CONCLUSIONS: In the brain, immune signaling molecules play a role in normal development that differs from their functions in inflammation and the immune response, although cellular receptors and signaling are shared. In adults, pro-inflammatory signals have emerged as contributing to brain adaptation in stress, depression, AUD, and neurodegenerative diseases. HMGB1, a cytokine-like signaling protein released from activated cells, including neurons, is hypothesized to activate pro-inflammatory signals through TLRs that contribute to adaptations to binge and chronic heavy drinking. HMGB1 alone and in heteromers with other molecules activates TLRs and other immune receptors that spread signaling across neurons and glia. Both blood and brain levels of HMGB1 increase with ethanol exposure. In rats, an adolescent intermittent ethanol (AIE) binge drinking model persistently increases brain HMGB1 and its receptors; alters microglia, forebrain cholinergic neurons, and neuronal networks; and increases alcohol drinking and anxiety while disrupting cognition. Studies of human postmortem AUD brain have found elevated levels of HMGB1 and TLRs. These signals reduce cholinergic neurons, whereas microglia, the brain\'s immune cells, are activated by binge drinking. Microglia regulate synapses through complement proteins that can change networks affected by AIE that increase drinking, contributing to risks for AUD. Anti-inflammatory drugs, exercise, cholinesterase inhibitors, and histone deacetylase epigenetic inhibitors prevent and reverse the AIE-induced pathology. Further, HMGB1 antagonists and other anti-inflammatory treatments may provide new therapies for alcohol misuse and AUD. Collectively, these findings suggest that restoring the innate immune signaling balance is central to recovering from alcohol-related pathology.
METHODS: The authors used the search terms \"HMGB1 protein,\" \"alcohol,\" and \"brain\" across PubMed, Scopus, and Embase to find articles published between 1991 and 2023.
UNASSIGNED: The database search found 54 references in PubMed, 47 in Scopus, and 105 in Embase. A total of about 100 articles were included.
CONCLUSIONS: In the brain, immune signaling molecules play a role in normal development that differs from their functions in inflammation and the immune response, although cellular receptors and signaling are shared. In adults, pro-inflammatory signals have emerged as contributing to brain adaptation in stress, depression, AUD, and neurodegenerative diseases. HMGB1, a cytokine-like signaling protein released from activated cells, including neurons, is hypothesized to activate pro-inflammatory signals through TLRs that contribute to adaptations to binge and chronic heavy drinking. HMGB1 alone and in heteromers with other molecules activates TLRs and other immune receptors that spread signaling across neurons and glia. Both blood and brain levels of HMGB1 increase with ethanol exposure. In rats, an adolescent intermittent ethanol (AIE) binge drinking model persistently increases brain HMGB1 and its receptors; alters microglia, forebrain cholinergic neurons, and neuronal networks; and increases alcohol drinking and anxiety while disrupting cognition. Studies of human postmortem AUD brain have found elevated levels of HMGB1 and TLRs. These signals reduce cholinergic neurons, whereas microglia, the brain\'s immune cells, are activated by binge drinking. Microglia regulate synapses through complement proteins that can change networks affected by AIE that increase drinking, contributing to risks for AUD. Anti-inflammatory drugs, exercise, cholinesterase inhibitors, and histone deacetylase epigenetic inhibitors prevent and reverse the AIE-induced pathology. Further, HMGB1 antagonists and other anti-inflammatory treatments may provide new therapies for alcohol misuse and AUD. Collectively, these findings suggest that restoring the innate immune signaling balance is central to recovering from alcohol-related pathology.
摘要：
目标：暴饮暴食(即消耗足够的酒精以达到80mg/dL的血液乙醇浓度，2小时内大约4-5杯)，特别是在青春期早期，可以促进饮酒和酒精相关问题的逐渐增加，这些问题发展成为慢性复发性疾病的强迫性使用，酒精使用障碍（AUD）。在过去的十年里，神经免疫信号已经被发现有助于酒精诱导的饮酒变化，心情,和神经变性。这篇综述提出了一个机制假设，支持高迁移率族盒蛋白1（HMGB1）和Toll样受体（TLR）信号作为酒精诱导的神经免疫信号跨神经胶质和神经元的关键元件。改变基因转录和突触，改变有助于AUD发展的神经元网络。这一假设可能有助于指导进一步的预防和治疗研究。
方法：作者使用搜索词“HMGB1蛋白，\"\"酒精,“和”大脑“跨越PubMed，Scopus,和Embase查找1991年至2023年之间发表的文章。
■数据库搜索在PubMed中找到54个引用，47在Scopus，105在Embase共包括约100篇文章。
结论：在大脑中，免疫信号分子在正常发育中发挥作用，不同于它们在炎症和免疫反应中的功能，尽管细胞受体和信号是共有的。在成年人中,促炎信号已经出现，有助于大脑适应压力，抑郁症,AUD,和神经退行性疾病。HMGB1，一种从活化细胞释放的细胞因子样信号蛋白，包括神经元，假设通过TLRs激活促炎信号，有助于适应暴饮暴食和慢性重度饮酒。单独的HMGB1和与其他分子的异聚体激活TLR和其他免疫受体,其在神经元和神经胶质中传播信号。HMGB1的血液和脑水平均随着乙醇暴露而增加。在老鼠身上,青少年间歇性乙醇（AIE）暴饮暴食模型持续增加大脑HMGB1及其受体;改变小胶质细胞，前脑胆碱能神经元，和神经元网络；增加饮酒和焦虑，同时破坏认知。人类死后AUD脑的研究发现HMGB1和TLR的水平升高。这些信号减少胆碱能神经元，而小胶质细胞，大脑的免疫细胞，被暴饮暴食激活。小胶质细胞通过补体蛋白调节突触，补体蛋白可以改变受AIE影响的网络，增加饮酒，为AUD带来风险。抗炎药,锻炼,胆碱酯酶抑制剂，和组蛋白去乙酰化酶表观遗传抑制剂可预防和逆转AIE诱导的病理。Further,HMGB1拮抗剂和其他抗炎治疗可能为酒精滥用和AUD提供新疗法。总的来说，这些发现表明,恢复先天免疫信号平衡是酒精相关病理恢复的关键.
方法：作者使用搜索词“HMGB1蛋白，\"\"酒精,“和”大脑“跨越PubMed，Scopus,和Embase查找1991年至2023年之间发表的文章。
■数据库搜索在PubMed中找到54个引用，47在Scopus，105在Embase共包括约100篇文章。
结论：在大脑中，免疫信号分子在正常发育中发挥作用，不同于它们在炎症和免疫反应中的功能，尽管细胞受体和信号是共有的。在成年人中,促炎信号已经出现，有助于大脑适应压力，抑郁症,AUD,和神经退行性疾病。HMGB1，一种从活化细胞释放的细胞因子样信号蛋白，包括神经元，假设通过TLRs激活促炎信号，有助于适应暴饮暴食和慢性重度饮酒。单独的HMGB1和与其他分子的异聚体激活TLR和其他免疫受体,其在神经元和神经胶质中传播信号。HMGB1的血液和脑水平均随着乙醇暴露而增加。在老鼠身上,青少年间歇性乙醇（AIE）暴饮暴食模型持续增加大脑HMGB1及其受体;改变小胶质细胞，前脑胆碱能神经元，和神经元网络；增加饮酒和焦虑，同时破坏认知。人类死后AUD脑的研究发现HMGB1和TLR的水平升高。这些信号减少胆碱能神经元，而小胶质细胞，大脑的免疫细胞，被暴饮暴食激活。小胶质细胞通过补体蛋白调节突触，补体蛋白可以改变受AIE影响的网络，增加饮酒，为AUD带来风险。抗炎药,锻炼,胆碱酯酶抑制剂，和组蛋白去乙酰化酶表观遗传抑制剂可预防和逆转AIE诱导的病理。Further,HMGB1拮抗剂和其他抗炎治疗可能为酒精滥用和AUD提供新疗法。总的来说，这些发现表明,恢复先天免疫信号平衡是酒精相关病理恢复的关键.
