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-γ [IFN-γ]) yet promoting M(interleukin-4 [IL-4]) effector functions. Mechanistically, creatine inhibited the induction of immune effector molecules, including iNOS, by suppressing IFN-γ-JAK-STAT1 transcription-factor signaling while supporting IL-4-STAT6-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-γ and IL-4.

中文翻译：

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Slc6a8介导的肌酸摄取和积累通过调节细胞因子反应来重新编程巨噬细胞极化。

巨噬细胞极化伴随着L-精氨酸代谢的急剧变化。两种L-精氨酸催化酶iNOS和精氨酸酶1分别是经典的和活化的巨噬细胞的特征鲜明的标志性分子。L-精氨酸的第三个代谢命运是肌酸的产生，肌酸是细胞能量储备的关键来源，但肌酸在免疫系统中的作用知之甚少。在这里，遗传，基因组，代谢和免疫学分析表明，肌酸可通过抑制M（干扰素-γ[IFN-γ]）而促进M（interleukin-4 [IL-4]）效应子功能来重编程巨噬细胞极化。从机械上讲，肌酸会抑制免疫效应分子（包括iNOS）的诱导，通过抑制IFN-γ-JAK-STAT1转录因子信号转导，同时通过促进染色质重塑来支持IL-4-STAT6激活的精氨酸酶1表达。消融肌酸转运蛋白Slc6a8消耗细胞内肌酸改变体内巨噬细胞介导的免疫反应。这些结果通过调节细胞对细胞因子（例如IFN-γ和IL-4）的反应，揭示了肌酸在巨噬细胞极化中未曾表征的作用。