代谢异常,特别是M1/M2巨噬细胞失衡,在各种疾病的发展中起关键作用,导致严重的炎症反应。本研究旨在探讨解偶联蛋白2(UCP2)在调节巨噬细胞极化中的作用,糖酵解,代谢重编程,活性氧(ROS)和炎症。原代人巨噬细胞首先极化为M1和M2亚型,这两种亚型通过慢病毒介导的UCP2过表达或敲低感染,其次是酶联免疫吸附测定,逆转录-定量PCR,免疫印迹和流式细胞术分析UCP2对糖酵解的影响,氧化磷酸化(OXPHOS),ROS产生和细胞因子分泌,分别。结果表明,UCP2在M1巨噬细胞中表达受到抑制,在M2巨噬细胞中表达增加,提示其在巨噬细胞极化中的调节作用。UCP2过表达降低巨噬细胞糖酵解,OXPHOS增加,ROS产量减少,并导致M1偏振向M2偏振的转换。该过程涉及NF-κB信号传导以调节细胞因子和趋化因子的分泌谱,并影响糖酵解的关键酶和维持线粒体稳态的关键因素(核呼吸因子1)的表达。UCP2敲低M2巨噬细胞通过促进糖酵解加剧炎症和氧化应激,糖酵解抑制剂2-脱氧葡萄糖减弱了。这些发现强调了UCP2在调节巨噬细胞极化中的关键作用,新陈代谢,炎症和氧化应激通过其对糖酵解的影响,为巨噬细胞驱动的炎症和代谢疾病的潜在治疗策略提供有价值的见解。
Metabolic abnormalities, particularly the M1/M2 macrophage imbalance, play a critical role in the development of various diseases, leading to severe inflammatory responses. The present study aimed to investigate the role of uncoupling protein 2 (
UCP2) in regulating macrophage polarization, glycolysis, metabolic reprogramming, reactive oxygen species (ROS) and inflammation. Primary human macrophages were first polarized into M1 and M2 subtypes, and these two subtypes were infected by lentivirus-mediated
UCP2 overexpression or knockdown, followed by enzyme-linked immunosorbent assay, reverse transcription-quantitative PCR, western blotting and flow cytometry to analyze the effects of UCP2 on glycolysis, oxidative phosphorylation (OXPHOS), ROS production and cytokine secretion, respectively. The results demonstrated that UCP2 expression was suppressed in M1 macrophages and increased in M2 macrophages, suggesting its regulatory role in macrophage polarization.
UCP2 overexpression decreased macrophage glycolysis, increased OXPHOS, decreased ROS production, and led to the conversion of M1 polarization to M2 polarization. This process involved NF-κB signaling to regulate the secretion profile of cytokines and chemokines and affected the expression of key enzymes of glycolysis and a key factor for maintaining mitochondrial homeostasis (nuclear respiratory factor 1).
UCP2 knockdown in M2 macrophages exacerbated inflammation and oxidative stress by promoting glycolysis, which was attenuated by the glycolysis inhibitor 2-deoxyglucose. These findings highlight the critical role of
UCP2 in regulating macrophage polarization, metabolism, inflammation and oxidative stress through its effects on glycolysis, providing valuable insights into potential therapeutic strategies for macrophage-driven inflammatory and metabolic diseases.