Zhang Yubo, Yang Wenbo, Kumagai Yutaro, Loza Martin, Yang Yitao, Park Sung-Joon, Nakai Kenta
Department of Computational Biology and Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology, Tokyo 305-0044, Japan.
Int J Mol Sci. 2024 Dec 26;26(1):111. doi: 10.3390/ijms26010111.
Macrophages undergo polarization, resulting in distinct phenotypes. These transitions, including de-/repolarization, lead to hysteresis, where cells retain genetic and epigenetic signatures of previous states, influencing macrophage function. We previously identified a set of interferon-stimulated genes (ISGs) associated with high lipid levels in macrophages that exhibited hysteresis following M1 polarization, suggesting potential alterations in lipid metabolism. In this study, we applied weighted gene co-expression network analysis (WGCNA) and conducted comparative analyses on 162 RNA-seq samples from de-/repolarized and lipid-loaded macrophages, followed by functional exploration. Our results demonstrate that during M1 hysteresis, the sustained high expression of Marco (SR-A6) enhances lipid uptake, while the suppression of Abca1/2 reduces lipid efflux, collectively leading to elevated intracellular lipid levels. This accumulation may compensate for reduced cholesterol biosynthesis and provide energy for sustained inflammatory responses and interferon signaling. Our findings elucidate the relationship between M1 hysteresis and lipid metabolism, contributing to understanding the underlying mechanisms of macrophage hysteresis.
巨噬细胞会发生极化，从而产生不同的表型。这些转变，包括去极化/再极化，会导致滞后现象，即细胞保留先前状态的遗传和表观遗传特征，从而影响巨噬细胞的功能。我们之前鉴定出一组与巨噬细胞中高脂质水平相关的干扰素刺激基因（ISG），这些基因在M1极化后表现出滞后现象，提示脂质代谢可能发生了潜在改变。在本研究中，我们应用加权基因共表达网络分析（WGCNA），并对来自去极化/再极化和脂质负载巨噬细胞的162个RNA测序样本进行了比较分析，随后进行了功能探索。我们的结果表明，在M1滞后期间，Marco（SR-A6）的持续高表达增强了脂质摄取，而Abca1/2的抑制则减少了脂质外流，共同导致细胞内脂质水平升高。这种积累可能补偿胆固醇生物合成的减少，并为持续的炎症反应和干扰素信号传导提供能量。我们的发现阐明了M1滞后与脂质代谢之间的关系，有助于理解巨噬细胞滞后的潜在机制。
