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Immunity. 2019 Aug 20;51(2):272-284.e7. doi: 10.1016/j.immuni.2019.06.007. Epub 2019 Aug 6.

Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses.

Author information

1
Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China; Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, 100084 Beijing, China.
2
School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, 100084 Beijing, China.
3
Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, 100084 Beijing, China.
4
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, NY 10021, USA.
5
Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China; Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
6
School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, 100084 Beijing, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 610041 Chengdu, China. Electronic address: ligongchen@tsinghua.edu.cn.
7
Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, 100084 Beijing, China. Electronic address: xiaoyuhu@tsinghua.edu.cn.

Abstract

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.

KEYWORDS:

L-arginine; Slc6a8; creatine; creatine transporter; immunometabolism; macrophage polarization

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