Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses
Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses
复制标题
Slc6a8介导的肌酸摄取和积累通过调节细胞因子反应重新编程巨噬细胞极化
DOI：
10.1016/j.immuni.2019.06.007
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发表时间：
2019-08-20
期刊：
影响因子：
32.4
通讯作者：
Hu, Xiaoyu
中科院分区：
文献类型：
--
作者：
Ji, Liangliang;Zhao, Xinbin;Hu, Xiaoyu
巨噬细胞极化伴随着L-精氨酸代谢的剧烈变化。两种L-精氨酸催化酶，iNOS和精氨酸酶1，分别是经典和交替激活的巨噬细胞的特征性标志分子。L-精氨酸的第三种代谢命运是生成肌酸，肌酸是细胞能量储备的关键来源，但对肌酸在免疫系统中的作用知之甚少。遗传、基因组、代谢和免疫学分析显示，肌酸通过抑制M（干扰素-γ [IFN-γ]）但促进M（白细胞介素-4 [IL-4]）效应器功能来重编程巨噬细胞极化。肌酸通过抑制IFN-γ-JAK-STAT 1转录因子信号传导抑制免疫效应分子（包括iNOS）的诱导，同时通过促进染色质重塑支持IL-4-STAT激活的转录酶1表达。通过消融肌酸转运蛋白Slc 6a 8来消耗细胞内肌酸改变了体内巨噬细胞介导的免疫应答。这些结果揭示了肌酸通过调节细胞对细胞因子如IFN-γ和IL-4的反应在巨噬细胞极化中的先前未表征的作用。
Macrophage polarization is accompanied by drastic changes in L-arginine metabolism. Two L-arginine catalytic enzymes, iNOS and arginase 1, are well-characterized hallmark molecules of classically and alternatively activated macrophages, respectively. The third metabolic fate of L-arginine is the generation of creatine that acts as a key source of cellular energy reserve, yet little is known about the role of creatine in the immune system. Here, genetic, genomic, metabolic, and immunological analyses revealed that creatine reprogrammed macrophage polarization by suppressing M(interferon-gamma [IFN-gamma]) yet promoting M(interleukin-4 [IL-4]) effector functions. Mechanistically, creatine inhibited the induction of immune effector molecules, including iNOS, by suppressing IFN-gamma-JAK-STAT1 transcription-factor signaling while supporting IL-4-STATE-activated arginase 1 expression by promoting chromatin remodeling. Depletion of intracellular creatine by ablation of the creatine transporter Slc6a8 altered macrophage-mediated immune responses in vivo. These results uncover a previously uncharacterized role for creatine in macrophage polarization by modulating cellular responses to cytokines such as IFN-gamma and IL-4.