Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha 410011, China.
Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
Int Immunopharmacol. 2024 Mar 30;130:111751. doi: 10.1016/j.intimp.2024.111751. Epub 2024 Feb 24.
Atherosclerosis (AS) is a continuously low-grade inflammatory disease, and monocyte-derived macrophages play a vital role in AS pathogenesis. Regulatory factor X1 (RFX1) has been reported to participate in differentiation of various cells. Our previous report showed that RFX1 expression in CD14 monocytes from AS patients was decreased and closely related to AS development. Macrophages mostly derive from monocytes and play an important role in AS plaque formation and stability. However, the functions of RFX1 in the formation of macrophage-derived foam cells and consequent AS development are unclear.
We explored the effects of RFX1 on oxidation low lipoprotein (ox-LDL)-stimulated foam cell formation and CD36 expression by increasing or silencing Rfx1 expression in mouse peritoneal macrophages (PMAs). The ApoERfx1 or ApoERfx1 Lyz2-Cre mice fed a high-fat diet for 24 weeks were used to further examine the effect of RFX1 on AS pathogenesis. We then performed dual luciferase reporter assays to study the regulation of RFX1 for CD36 transcription.
Our results demonstrate that RFX1 expression was significantly reduced in ox-LDL induced foam cells and negatively correlated with lipid uptake in macrophages. Besides, Rfx1 deficiency in myeloid cells aggravated atherosclerotic lesions in ApoE mice. Mechanistically, RFX1 inhibited CD36 expression by directly regulating CD36 transcription in macrophages.
The reduction of RFX1 expression in macrophages is a vital determinant for foam cell formation and the initiation of AS, proving a potential novel approach for the treatment of AS disease.
动脉粥样硬化（AS）是一种持续的低度炎症性疾病，单核细胞衍生的巨噬细胞在 AS 发病机制中起着至关重要的作用。调节因子 X1（RFX1）已被报道参与各种细胞的分化。我们之前的报告显示，AS 患者 CD14 单核细胞中 RFX1 的表达减少，与 AS 的发展密切相关。巨噬细胞主要来源于单核细胞，在 AS 斑块形成和稳定性中发挥重要作用。然而，RFX1 在巨噬细胞源性泡沫细胞形成中的功能以及随后的 AS 发展尚不清楚。
我们通过增加或沉默小鼠腹腔巨噬细胞（PMAs）中的 Rfx1 表达，探讨了 RFX1 对氧化型低密度脂蛋白（ox-LDL）刺激的泡沫细胞形成和 CD36 表达的影响。用高脂饮食喂养 ApoERfx1 或 ApoERfx1 Lyz2-Cre 小鼠 24 周，进一步研究 RFX1 对 AS 发病机制的影响。然后，我们进行双荧光素酶报告基因检测，研究 RFX1 对 CD36 转录的调节作用。
我们的结果表明，RFX1 表达在 ox-LDL 诱导的泡沫细胞中显著降低，与巨噬细胞中的脂质摄取呈负相关。此外，髓系细胞中 Rfx1 的缺失加剧了 ApoE 小鼠的动脉粥样硬化病变。在机制上，RFX1 通过直接调节巨噬细胞中 CD36 的转录来抑制 CD36 的表达。
巨噬细胞中 RFX1 表达的减少是泡沫细胞形成和 AS 起始的重要决定因素，为 AS 疾病的治疗提供了一种新的潜在方法。
