Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model.

IF 3.5 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Biology Pub Date : 2024-11-08 DOI:10.1126/sciadv.ado5820

Xindi Li, Jiayi Liu, Andrew J Boreland, Sneha Kapadia, Siwei Zhang, Alessandro C Stillitano, Yara Abbo, Lorraine Clark, Dongbing Lai, Yunlong Liu, Peter B Barr, Jacquelyn L Meyers, Chella Kamarajan, Weipeng Kuang, Arpana Agrawal, Paul A Slesinger, Danielle Dick, Jessica Salvatore, Jay Tischfield, Jubao Duan, Howard J Edenberg, Anat Kreimer, Ronald P Hart, Zhiping P Pang

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Abstract

Polygenic risk scores (PRSs) assess genetic susceptibility to alcohol use disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as notable contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with AUD high-PRS (diagnosed with AUD) or low-PRS (unaffected). Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between high-PRS and low-PRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; high-PRS microglial cells displayed enhanced phagocytosis and increased CLEC7A expression, unlike low-PRS microglial cells. Synapse numbers in cocultures of induced neurons with microglia after alcohol exposure were lower in high-RPS cocultures, suggesting possible excess synapse pruning. This study provides insights into the intricate relationship between AUD PRS, ethanol, and microglial function, potentially influencing neuronal functions in developing AUD.

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在人类小胶质细胞模型中，酒精使用障碍的多基因风险会影响细胞对乙醇暴露的反应。

多基因风险评分（PRSs）可评估酒精使用障碍（AUD）的遗传易感性，但其分子影响仍未得到充分探索。神经免疫相互作用，尤其是小胶质细胞中的神经免疫相互作用，被认为是导致 AUD 病理生理学的重要因素。我们研究了 AUD PRS 和乙醇在人类小胶质细胞中的相互作用，这些小胶质细胞来自 AUD 高 PRS（确诊为 AUD）或低 PRS（未受影响）患者的 iPSCs。乙醇暴露会诱导小胶质细胞中 CD68 表达的升高和形态学变化，高 PRS 和低 PRS 小胶质细胞的反应有所不同。转录组分析表明，乙醇暴露后，MHCII复合体和吞噬相关基因的表达存在差异；高PRS小胶质细胞的吞噬能力增强，CLEC7A的表达增加，而低PRS小胶质细胞则不同。酒精暴露后，在诱导神经元与小胶质细胞的共培养物中，高RPS共培养物的突触数量较低，这表明可能存在过度的突触修剪。本研究揭示了 AUD PRS、乙醇和小胶质细胞功能之间错综复杂的关系，可能会影响发育中的 AUD 神经元功能。

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来源期刊

ACS Chemical Biology 生物-生化与分子生物学

CiteScore

7.50

自引率

5.00%

发文量

353

审稿时长

3.3 months

期刊介绍： ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.