Citations 2
UK5099 inhibits macrophage activation independent of mitochondrial pyruvate carrier mediated metabolism
Ran, Linyu, Zhang, Song , Zhou, Jiaqi , Gan, Haiyun , Li, Qiang , Herrmann, Joerg , Zhang, Song , Ran, Linyu, Zhao, Pei , Jeon, Ryoung‐Hoon , Wang, Feilong
No container title available | September 10, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis culminates in the production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by conversion to citrate and utilization in the TCA cycle. Alternatively, pyruvate can be metabolized to lactate under aerobic conditions, which had been considered to be the dominant route in the setting of classical macrophage activation. However, based on studies that used UK5099 as a MPC inhibitor and showed reduction in key inflammatory cytokines, the mitochondrial route has been considered to be of significance for M1 activation as well. Herein, using a genetic depletion model, we found that MPC is dispensable for metabolic reprogramming and the activation of M1. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2–5µM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Apart from MPC inhibition, UK5099 at high doses impairs glutamate oxidation, mitochondrial membrane potential and HIF-1α stabilization. Taken together, UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.
Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1
Gao, Yayi , Tang, Jiayou , Li, Qiang , Nie, Jia , Lin, Fang , Wu, Qingsi, Chen, Zuojia , Gao, Zhimei, Fan, Huimin , Tsun, Andy , Shen, Jijia, Chen, Guihua , Liu, Zhongmin , Olsen, Nancy J. , Zheng, Song Guo , Li, Bin , Chen, Weiqian , Lou, Zhenkun
Proceedings of the National Academy of Sciences | June 10, 2015 | Volume: 112 | Issue: 25 | Pages: No page available
Significance Treg cells suppress excessive and aberrant immune responses. Impaired function or homeostasis of Treg cells would induce severe autoimmune and inflammatory diseases. Forkhead box P3 (FOXP3), as a master regulator of Treg cells, forms a large complex with other binding factors to modulate Treg-cell function subtly in pathological and physiological conditions. We identified that Deleted in breast cancer 1 (DBC1) is an essential subunit of the FOXP3 complex in human CD4 + Treg cells. Our results show that the inflammatory cytokines TNF-α or IL-6 trigger FOXP3 degradation, whereas downregulation of DBC1 expression prevents FOXP3 degradation and maintains Treg-cell function under inflammatory stimuli in vitro and in vivo. These findings unveil a previously unidentified pathway for therapeutically modulating FOXP3 + Treg-cell stability under inflammation.