Muffova Barbora, Kauerova Sona, Paukner Karel, Bartuskova Hana, Poledne Rudolf, Kralova Lesna Ivana
Laboratory for Atherosclerosis Research, Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic.
Sci Rep. 2025 Jun 2;15(1):19237. doi: 10.1038/s41598-025-02418-9.
The study focuses on the effects of fluvastatin on immunomarkers of the M1 and M2 macrophages and its direct role in macrophage (M0) polarization. Moreover, it investigates the dependency of immunomodulatory properties of fluvastatin on the mevalonate pathway. Macrophages (M0, M1, M2), differentiated from human blood monocytes, were treated with fluvastatin. Mevalonate and geranylgeranyl pyrophosphate intermediates were introduced to assess the mevalonate pathway dependence. The immunomarkers were evaluated with qPCR, ELISA, Griess assay, and flow cytometry. Fluvastatin significantly reduces the pro-inflammatory gene expression (NFκB, IL-1β, IL-6, iNOS) in M1 while enhancing the anti-inflammatory markers (Arg-1, TGFβ) in M2 macrophages. The production of the TNFα, IL-1β, and IL-6 cytokines is reduced in M1, and IL-10 production increased in M2 macrophages. Fluvastatin decreases the iNOS activity in M1 macrophages. The intermediates reverse the fluvastatin's effects on anti-inflammatory gene expression by M2 macrophages, cytokine production (by M1 and M2 macrophages), and iNOS activity (by M1 macrophages). Their impact on surface marker expression was somewhat limited. These findings demonstrate that fluvastatin exerts anti-inflammatory effects on polarized macrophages without affecting polarization per se and also highlight the dependency on the mevalonate pathway. This study deepens the understanding of statins' immunomodulatory mechanisms, suggesting potential applications in treating inflammatory diseases.
该研究聚焦于氟伐他汀对M1和M2巨噬细胞免疫标志物的影响及其在巨噬细胞（M0）极化中的直接作用。此外，还研究了氟伐他汀免疫调节特性对甲羟戊酸途径的依赖性。用氟伐他汀处理从人血单核细胞分化而来的巨噬细胞（M0、M1、M2）。引入甲羟戊酸和香叶基香叶基焦磷酸中间体以评估对甲羟戊酸途径的依赖性。通过qPCR、ELISA、Griess测定法和流式细胞术评估免疫标志物。氟伐他汀显著降低M1中促炎基因的表达（NFκB、IL-1β、IL-6、iNOS），同时增强M2巨噬细胞中的抗炎标志物（Arg-1、TGFβ）。M1中TNFα、IL-1β和IL-6细胞因子的产生减少，M2巨噬细胞中IL-10的产生增加。氟伐他汀降低M1巨噬细胞中的iNOS活性。这些中间体可逆转氟伐他汀对M2巨噬细胞抗炎基因表达、细胞因子产生（M1和M2巨噬细胞）和iNOS活性（M1巨噬细胞）的影响。它们对表面标志物表达的影响在一定程度上有限。这些发现表明，氟伐他汀对极化巨噬细胞具有抗炎作用，而不影响其本身的极化，同时也突出了对甲羟戊酸途径的依赖性。这项研究加深了对他汀类药物免疫调节机制的理解，提示了其在治疗炎症性疾病中的潜在应用。
