Lewis Sloan A, Sureshchandra Suhas, Doratt Brianna, Jimenez Vanessa A, Stull Cara, Grant Kathleen A, Messaoudi Ilhem
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, United States.
Institute for Immunology, University of California, Irvine, CA, United States.
Front Immunol. 2021 Aug 20;12:724015. doi: 10.3389/fimmu.2021.724015. eCollection 2021.
Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilized a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to LPS stimulation, their response to was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia () and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets skewed towards inflammatory phenotypes was complemented by epigenetic analysis, which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Collectively, data presented in this manuscript demonstrate that CHD shifts classical monocyte subset composition and primes the monocytes towards a more hyper-inflammatory response to LPS, but compromised pathogen response.
长期大量饮酒是已知的易患细菌和病毒感染以及伤口愈合受损的风险因素。有证据表明，这些缺陷是由源自髓样细胞（尤其是单核细胞和巨噬细胞）的炎症反应失调介导的，但其机制仍知之甚少。我们对长期大量饮酒的研究能力受到人类饮酒模式和行为的复杂性以及酒精使用障碍患者的合并症和混杂风险因素的影响。为了克服这些挑战，我们利用了一种自愿乙醇自我给药的恒河猴转化模型，该模型密切模拟了人类饮酒模式和慢性情况。在本研究中，我们在每日摄入乙醇12个月后，检查了长期大量饮酒对对照和长期大量饮酒雌性猕猴血液单核细胞的影响。虽然长期大量饮酒雌性猕猴的单核细胞对脂多糖刺激产生了过度炎症反应，但其对[此处原文缺失内容]的反应受到抑制。对纯化单核细胞进行的深度单细胞RNA测序分析显示，经典单核细胞亚群发生了显著变化，在长期大量饮酒的猕猴中，表达缺氧（[此处原文缺失内容]）和炎症（NFkB信号通路）标志物的细胞积累。单核细胞亚群向炎症表型的倾斜增加，这一点得到了表观遗传分析的补充，表观遗传分析显示，调节细胞因子信号通路相关基因的启动子区域具有更高的可及性。本手稿中的数据共同表明，长期大量饮酒会改变经典单核细胞亚群组成，并使单核细胞对脂多糖产生更强的过度炎症反应，但病原体反应受损。
