Podleśny-Drabiniok Anna, Romero-Molina Carmen, Patel Tulsi, See Wen Yi, Liu Yiyuan, Marcora Edoardo, Goate Alison M
Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; Sanford Grossman Interdisciplinary Program In Neural Circuitry and Immune Function, New York, NY 10029, USA.
Cell Rep. 2025 Jul 22;44(7):115909. doi: 10.1016/j.celrep.2025.115909. Epub 2025 Jun 25.
Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.
包括脑内常驻小胶质细胞和外周巨噬细胞在内的髓样细胞在诸如阿尔茨海默病（AD）等神经退行性疾病中发挥着关键作用。由于缺乏强大的体外模型，对它们与疾病相关状态的研究受到限制。在此，我们测试了一种细胞因子混合物（白细胞介素[IL]-4、集落刺激因子1、IL-34和转化生长因子-β）是否能将人THP-1巨噬细胞重编程为与AD相关的表型。这种处理诱导了显著的转录组变化，促使THP-1巨噬细胞朝着一种转录状态转变，这种状态让人联想到疾病相关小胶质细胞和脂质相关巨噬细胞（LAM），统称为DLAM。转录组分析揭示了与氧化磷酸化、溶酶体功能和脂质代谢相关的基因表达变化。单细胞RNA测序显示，在细胞因子混合物处理的THP-1巨噬细胞中，DLAM簇的比例增加。功能分析表明细胞运动性、吞噬作用、溶酶体活性和代谢谱发生了改变。这些发现为细胞因子介导的巨噬细胞重编程为与疾病相关状态提供了见解，突出了它们在神经退行性疾病中的作用以及治疗开发的潜力。
