Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.
Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.
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酒精使用障碍（AUD）与细胞脂多糖挑战的敏感性增强有关。
DOI：
10.1111/acer.15173
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Irwin,MichaelR
中科院分区：
文献类型：
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作者：
Burnette,ElizabethM;Grodin,EricaN;Olmstead,Richard;Ray,LaraA;Irwin,MichaelR
背景炎症与酒精使用障碍(AUD)有关。一种新的表征AUD相关免疫信号的方法包括探测Toll样受体(TLR)-4通过内毒素(LPS)刺激单核细胞产生细胞内细胞因子(ICCs)。我们分析了36名受试者(AUDN= 14；对照组N= 22)在不同时间采集的血样，分别在静息(即未刺激)和内毒素刺激后(即每名参与者重复5次非刺激或刺激措施)评估了ICC的表达。检测指标包括肿瘤坏死因子-α、白介素6、肿瘤坏死因子-α和白介素6共表达、干扰素。对于每个标记，我们构建了以澳元、脂多糖和时间点为固定效应(以BMI为协变量)的线性混合模型，允许随机斜率和截距。结果对于TLR4刺激的单核细胞产生 - ，存在AUD(p<；α)、 (p<； 0.001)和AUD × Lps的交互作用(p<； 0.05)，提示AUD患者单核细胞有更强的未刺激和刺激的肿瘤坏死因子α的表达。同样，对于TLR4刺激的单核细胞共表达肿瘤坏死因子-α和IL-6，存在AUD(p<； 0.01)、内毒素(p<； 0.001)和AUD × 内毒素相互作用(p<； 0.05)的影响。对IL-6和肿瘤坏死因子-α/IL-6共表达有时点效应(p<； 0.001)。对于干扰素，AUD(p<； 0.001)、内毒素(p<； 0.001)和AUD × LPS(p<； 0.001)也有影响。结论AUD患者单核细胞静息或未刺激时表达α和IL-6/α共表达水平均高于对照组。AUD与TLR4刺激的单核细胞产生肿瘤坏死因子-α的增加以及IL-6和肿瘤坏死因子-α的共同产生有关。据我们所知，这是第一个研究AUD和单核细胞产生促炎细胞因子之间的关系的研究，这些细胞在静息状态下和对内毒素刺激TLR4的反应中。这项研究扩展了先前关于促炎细胞因子在AUD中的作用的发现，并为使用这一方法探索AUD背后的神经免疫机制提供了关键的概念证明。
BackgroundInflammation has been associated with alcohol use disorder (AUD). A novel method to characterize AUD‐related immune signaling involves probing Toll‐like receptor (TLR)‐4 stimulated monocyte production of intracellular cytokines (ICCs) via lipopolysaccharide (LPS). We evaluated relationships between AUD and ICC production at rest and after LPS stimulation.MethodsWe analyzed blood samples from 36 participants (AUDN= 14; ControlsN= 22), collected across time, with ICC expression assessed at rest (i.e., unstimulated) and following stimulation with LPS (i.e., a total of 5 repeated unstimulated or stimulated measures/participant). Markers assessed included tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), TNF‐α and IL‐6 co‐expression, and interferon (IFN). For each marker, we constructed linear mixed models with AUD, LPS, and timepoint as fixed effects (BMI as covariate), allowing for random slope and intercept. AUD × LPS was included as an interaction.ResultsFor TLR4‐stimulated monocyte production of TNF‐α, there were effects of AUD (p< 0.01), LPS (p< 0.001), and AUD × LPS interaction (p< 0.05), indicating that individuals with AUD showed greater unstimulated‐ and stimulated monocyte expression of TNF‐α. Similarly, for TLR4‐stimulated monocyte co‐expression of TNF‐α and IL‐6, there were effects of AUD (p< 0.01), LPS (p< 0.001), and AUD × LPS interaction (p< 0.05). No AUD or LPS effects were found for IL‐6. Timepoint effects were observed on IL‐6 and TNF‐α/IL‐6 co‐expression (p< 0.001). Finally, for IFN there were also effects of AUD (p< 0.05), LPS (p< 0.001), and AUD × LPS (p< 0.001).ConclusionsIndividuals with AUD showed greater resting or unstimulated levels of intracellular monocyte expression of TNF‐α and IL‐6/TNF‐α co‐expression than controls. AUD was associated with increases in TLR4‐stimulated monocyte production of TNF‐α and co‐production of IL‐6 and TNF‐α. This is, to our knowledge, the first study to investigate relationships between AUD and monocyte production of proinflammatory cytokines, at rest and in response to TLR4 stimulation with LPS. The study extends previous findings on the roles of proinflammatory cytokines in AUD and serves as a critical proof of concept for the use of this method to probe neuroimmune mechanisms underlying AUD.