Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167524. doi: 10.1016/j.bbadis.2024.167524. Epub 2024 Sep 20.
Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.
患有长链脂肪酸氧化（lcFAO）机制遗传障碍的患者表现出疾病表现的异质性，症状的加重通常是由炎症激活引发的。单核细胞和巨噬细胞是先天免疫细胞，在炎症的发生和消退中起着重要作用。这些细胞在激活时会进行代谢重排，包括调节 FAO 速率。FAO 的重排以及 lcFAO 障碍（lcFAOD）对人单核细胞和巨噬细胞表型和功能的影响在很大程度上仍然未知。在这里，我们对循环单核细胞进行了广泛的表型分析，并分析了 11 名 lcFAOD 患者和 11 名匹配对照者的血浆细胞因子水平。在 lcFAOD 患者中，我们观察到诱导性血浆炎症细胞因子 IL-1β 和 IL-6 水平升高，并观察到循环单核细胞亚群中 CD206 和 CD62L 表面标记物表达增强。为了模拟最常见的 lcFAOD 极长链酰基辅酶 A 脱氢酶障碍（VLCADD），我们使用 siRNA 介导的健康志愿者来源的巨噬细胞中 ACADVL 基因（编码 VLCAD）的敲低。由此，我们发现 siVLCAD 影响 IL-4 诱导的替代巨噬细胞激活，同时保持 LPS 反应和细胞代谢完整。同样，来自 lcFAOD 患者的单核细胞衍生的巨噬细胞具有升高的 IL-4 诱导的替代巨噬细胞标志物 CD206 和 CD200R。尽管如此，它们没有表现出主要的代谢缺陷或 LPS 诱导的炎症反应变化。我们的结果表明，来自 lcFAOD 患者的单核细胞和巨噬细胞没有表现出主要的炎症或代谢差异，并表明 IL-4 诱导的表面标志物与人巨噬细胞中的 lcFAO 交织在一起。
