Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, West Yanta Road No.76, Xi'an, Shaanxi, 710061, China; National & Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, China.
Institute of Molecular and Translational Medicine, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, West Yanta Road No.76, Xi'an, Shaanxi, 710061, China; Yangling Demonstration Zone Hospital, Xianyang, Shaanxi, 712100, China.
Exp Cell Res. 2021 Jan 1;398(1):112404. doi: 10.1016/j.yexcr.2020.112404. Epub 2020 Nov 24.
Pristane-induced arthritis (PIA) could be adoptively transferred by splenic T cells in rats, and innate immunity should play critical roles in T cell activation. However, in pre-clinical stage, the activation mechanism of innate cells like macrophages remains unclear. Here we found that PIA was dependent on macrophages since cell depletion alleviated disease severity. Splenic macrophages of PIA rats showed M1 phenotypic shifting. The quantitative proteomics analysis suggested that macrophages initiated metabolic reprogramming with the conversion of aerobic oxidation to glycolysis in response to pristane in vivo. Notably, macrophages treated with pristane showed mitochondrial dysregulation and increased glycolysis flux and enzyme activity. Additionally, TNFα production, strongly associating with the glycolysis enzyme Ldha/Ldhb, could be reduced as glycolysis was inhibited or be enhanced as citrate cycle was blocked. This work provides detailed insights into the molecular mechanisms of pristane-mediated metabolic reprogramming in macrophages and suggests a new therapeutic strategy for arthritic disorders.
角鲨烷诱导的关节炎（PIA）可在大鼠中通过脾 T 细胞被动转移，固有免疫应在 T 细胞激活中起关键作用。然而，在临床前阶段，巨噬细胞等固有细胞的激活机制尚不清楚。在这里，我们发现 PIA 依赖于巨噬细胞，因为细胞耗竭可减轻疾病严重程度。PIA 大鼠的脾巨噬细胞表现出 M1 表型转变。定量蛋白质组学分析表明，巨噬细胞在体内用角鲨烷诱导下，通过有氧氧化向糖酵解转化，启动代谢重编程。值得注意的是，用角鲨烷处理的巨噬细胞表现出线粒体功能失调和糖酵解通量增加以及酶活性增强。此外，TNFα 的产生与糖酵解酶 Ldha/Ldhb 强烈相关，当糖酵解被抑制时，TNFα 的产生减少，当柠檬酸循环被阻断时，TNFα 的产生增加。这项工作提供了角鲨烷介导的巨噬细胞代谢重编程的分子机制的详细见解，并为关节炎疾病提出了一种新的治疗策略。
