Chaparro Visnu, Leroux Louis-Philippe, Lebourg Aurore, Chagneau Sophie, Graber Tyson E, Alain Tommy, Jaramillo Maritza
Institut National de la Recherche Scientifique (INRS) - Centre Armand-Frappier Santé Biotechnologie (CAFSB), 531 boul. des Prairies, Laval, QC H7V 1B7, Canada.
Children's Hospital of Eastern Ontario Research Institute, 401 Smith Rd. Ottawa, ON K1H 8L1, Canada.
J Leukoc Biol. 2024 Dec 31;117(1). doi: 10.1093/jleuko/qiae178.
Leukemia inhibitory factor, a member of the interleukin-6 cytokine family, plays a central role in homeostasis and disease. Interestingly, some of the pleiotropic effects of leukemia inhibitory factor have been attributed to the modulation of macrophage functions although the molecular underpinnings have not been explored at a genome-wide scale. Herein, we investigated leukemia inhibitory factor-driven transcriptional changes in murine bone marrow-derived macrophages by RNA sequencing. In silico analyses revealed a selective and time-dependent remodeling of macrophage gene expression programs associated with lipid metabolism and cell activation. Accordingly, a subset of leukemia inhibitory factor-upregulated transcripts related to cholesterol metabolism and lipid internalization was validated by real-time quantitative polymerase chain reaction. This was accompanied by a leukemia inhibitory factor-enhanced capacity for lipid accumulation in macrophages upon incubation with oxidized low-density lipoprotein. Mechanistically, leukemia inhibitory factor triggered the phosphorylation (Y705 and S727) and nuclear translocation of the transcription factor STAT3 in bone marrow-derived macrophages. Consistent with this, ingenuity pathway analysis identified STAT3 as an upstream regulator of a subset of transcripts, including Il4ra, in leukemia inhibitory factor-treated macrophages. Notably, leukemia inhibitory factor priming enhanced bone marrow-derived macrophage responses to interleukin-4-mediated M2 polarization (i.e. increased arginase activity and accumulation of transcripts encoding for M2 markers). Conversely, leukemia inhibitory factor stimulation had no significant effect in bone marrow-derived macrophage responses to M1-polarizing stimuli (interferon-γ and lipopolysaccharide). Thus, our study provides insight into the transcriptional landscape of leukemia inhibitory factor-treated macrophages, shedding light on its role in lipid metabolism and M2 polarization responses. A better understanding of the regulatory mechanisms governing leukemia inhibitory factor-driven changes might help informing novel therapeutic approaches aiming to reprogram macrophage phenotypes in diseased states (e.g. cancer, atherosclerosis, and infection).
白血病抑制因子是白细胞介素-6细胞因子家族的成员，在体内稳态和疾病中起核心作用。有趣的是，白血病抑制因子的一些多效性作用归因于巨噬细胞功能的调节，尽管尚未在全基因组范围内探索其分子基础。在此，我们通过RNA测序研究了白血病抑制因子驱动的小鼠骨髓来源巨噬细胞中的转录变化。计算机分析揭示了与脂质代谢和细胞激活相关的巨噬细胞基因表达程序的选择性和时间依赖性重塑。因此，通过实时定量聚合酶链反应验证了与胆固醇代谢和脂质内化相关的白血病抑制因子上调转录本的一个子集。这伴随着白血病抑制因子增强了巨噬细胞在与氧化型低密度脂蛋白孵育后脂质积累的能力。从机制上讲，白血病抑制因子触发了骨髓来源巨噬细胞中转录因子STAT3的磷酸化（Y705和S727）和核转位。与此一致， Ingenuity通路分析确定STAT3是白血病抑制因子处理的巨噬细胞中包括Il4ra在内的转录本子集的上游调节因子。值得注意的是，白血病抑制因子预处理增强了骨髓来源巨噬细胞对白介素-4介导的M2极化的反应（即精氨酸酶活性增加和编码M2标志物的转录本积累）。相反，白血病抑制因子刺激对骨髓来源巨噬细胞对M1极化刺激（干扰素-γ和脂多糖）的反应没有显著影响。因此，我们的研究深入了解了白血病抑制因子处理的巨噬细胞的转录图谱，揭示了其在脂质代谢和M2极化反应中的作用。更好地理解控制白血病抑制因子驱动变化的调节机制可能有助于为旨在在疾病状态（如癌症、动脉粥样硬化和感染）中重新编程巨噬细胞表型的新型治疗方法提供信息。
