IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42277-4.html
   My bibliography  Save this article

Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation

Author

Listed:
  • Marlies Cortés

    (Cell Plasticity, Differentiation, and Cancer, IDIBAPS)

  • Agnese Brischetto

    (Cell Plasticity, Differentiation, and Cancer, IDIBAPS)

  • M. C. Martinez-Campanario

    (Cell Plasticity, Differentiation, and Cancer, IDIBAPS)

  • Chiara Ninfali

    (Cell Plasticity, Differentiation, and Cancer, IDIBAPS)

  • Verónica Domínguez

    (National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco)

  • Sara Fernández

    (Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER)

  • Raquel Celis

    (Hospital Clínic and IDIBAPS)

  • Anna Esteve-Codina

    (National Center for Genomics Analysis (CNAG))

  • Juan J. Lozano

    (Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute)

  • Julia Sidorova

    (Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute)

  • Gloria Garrabou

    (Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER)

  • Anna-Maria Siegert

    (University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital)

  • Carlos Enrich

    (University of Barcelona School of Medicine and Health Sciences)

  • Belén Pintado

    (National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco)

  • Manuel Morales-Ruiz

    (Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute
    University of Barcelona School of Medicine and Health Sciences
    Hospital Clínic of Barcelona and IDIBAPS)

  • Pedro Castro

    (Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER)

  • Juan D. Cañete

    (Hospital Clínic and IDIBAPS)

  • Antonio Postigo

    (Cell Plasticity, Differentiation, and Cancer, IDIBAPS
    Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute
    J.G. Brown Cancer Center
    ICREA)

Abstract

Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.

Suggested Citation

  • Marlies Cortés & Agnese Brischetto & M. C. Martinez-Campanario & Chiara Ninfali & Verónica Domínguez & Sara Fernández & Raquel Celis & Anna Esteve-Codina & Juan J. Lozano & Julia Sidorova & Gloria Gar, 2023. "Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42277-4
    DOI: 10.1038/s41467-023-42277-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42277-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-42277-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Di Zhang & Zhanyun Tang & He Huang & Guolin Zhou & Chang Cui & Yejing Weng & Wenchao Liu & Sunjoo Kim & Sangkyu Lee & Mathew Perez-Neut & Jun Ding & Daniel Czyz & Rong Hu & Zhen Ye & Maomao He & Y. Ge, 2019. "Metabolic regulation of gene expression by histone lactylation," Nature, Nature, vol. 574(7779), pages 575-580, October.
    2. Zenan Wang & Binghao Li & Shan Li & Wenlong Lin & Zhan Wang & Shengdong Wang & Weida Chen & Wei Shi & Tao Chen & Hao Zhou & Eloy Yinwang & Wenkan Zhang & Haochen Mou & Xupeng Chai & Jiahao Zhang & Zhi, 2022. "Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. John J. Seeley & Rebecca G. Baker & Ghait Mohamed & Tony Bruns & Matthew S. Hayden & Sachin D. Deshmukh & Daniel E. Freedberg & Sankar Ghosh, 2018. "Induction of innate immune memory via microRNA targeting of chromatin remodelling factors," Nature, Nature, vol. 559(7712), pages 114-119, July.
    4. Marisa W. Friederich & Sharita Timal & Christopher A. Powell & Cristina Dallabona & Alina Kurolap & Sara Palacios-Zambrano & Drago Bratkovic & Terry G. J. Derks & David Bick & Katelijne Bouman & Kathr, 2018. "Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Tianshi Feng & Xuemei Zhao & Ping Gu & Wah Yang & Cunchuan Wang & Qingyu Guo & Qiaoyun Long & Qing Liu & Ying Cheng & Jin Li & Cynthia Kwan Yui Cheung & Donghai Wu & Xinyu Kong & Yong Xu & Dewei Ye & , 2022. "Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Hanyang Dong & Jianji Zhang & Hui Zhang & Yue Han & Congcong Lu & Chen Chen & Xiaoxia Tan & Siyu Wang & Xue Bai & Guijin Zhai & Shanshan Tian & Tao Zhang & Zhongyi Cheng & Enmin Li & Liyan Xu & Kai Zh, 2022. "YiaC and CobB regulate lysine lactylation in Escherichia coli," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Lianhui Sun & Yuan Zhang & Boyu Yang & Sijun Sun & Pengshan Zhang & Zai Luo & Tingting Feng & Zelin Cui & Ting Zhu & Yuming Li & Zhengjun Qiu & Guangjian Fan & Chen Huang, 2023. "Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Yusuke Nasu & Abhi Aggarwal & Giang N. T. Le & Camilla Trang Vo & Yuki Kambe & Xinxing Wang & Felix R. M. Beinlich & Ashley Bomin Lee & Tina R. Ram & Fangying Wang & Kelsea A. Gorzo & Yuki Kamijo & Ma, 2023. "Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Zhenzhen Chen & Qiankun He & Tiankun Lu & Jiayi Wu & Gaoli Shi & Luyun He & Hong Zong & Benyu Liu & Pingping Zhu, 2023. "mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Javier Botey-Bataller & Hedwig D. Vrijmoeth & Jeanine Ursinus & Bart-Jan Kullberg & Cees C. Wijngaard & Hadewych Hofstede & Ahmed Alaswad & Manoj K. Gupta & Lennart M. Roesner & Jochen Huehn & Thomas , 2024. "A comprehensive genetic map of cytokine responses in Lyme borreliosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Han Wang & Huiying Sun & Bilin Liang & Fang Zhang & Fan Yang & Bowen Cui & Lixia Ding & Xiang Wang & Ronghua Wang & Jiaoyang Cai & Yanjing Tang & Jianan Rao & Wenting Hu & Shuang Zhao & Wenyan Wu & Xi, 2023. "Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Shan Yao & Min-Dong Xu & Ying Wang & Shen-Ting Zhao & Jin Wang & Gui-Fu Chen & Wen-Bing Chen & Jian Liu & Guo-Bin Huang & Wen-Juan Sun & Yan-Yan Zhang & Huan-Li Hou & Lei Li & Xiang-Dong Sun, 2023. "Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Ziping Niu & Chen Chen & Siyu Wang & Congcong Lu & Zhiyue Wu & Aiyuan Wang & Jing Mo & Jianji Zhang & Yanpu Han & Ye Yuan & Yingao Zhang & Yong Zang & Chaoran He & Xue Bai & Shanshan Tian & Guijin Zha, 2024. "HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Markus M. Rinschen & Oleg Palygin & Ashraf El-Meanawy & Xavier Domingo-Almenara & Amelia Palermo & Lashodya V. Dissanayake & Daria Golosova & Michael A. Schafroth & Carlos Guijas & Fatih Demir & Johan, 2022. "Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    11. Fjodor Merkuri & Megan Rothstein & Marcos Simoes-Costa, 2024. "Histone lactylation couples cellular metabolism with developmental gene regulatory networks," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    12. Chi Zhou & Wenxin Li & Zhenxing Liang & Xianrui Wu & Sijing Cheng & Jianhong Peng & Kaixuan Zeng & Weihao Li & Ping Lan & Xin Yang & Li Xiong & Ziwei Zeng & Xiaobin Zheng & Liang Huang & Wenhua Fan & , 2024. "Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    13. Veronica L. Li & Shuke Xiao & Pascal Schlosser & Nora Scherer & Amanda L. Wiggenhorn & Jan Spaas & Alan Sheng-Hwa Tung & Edward D. Karoly & Anna Köttgen & Jonathan Z. Long, 2024. "SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    14. Hanjie Zhang & Yitong Zhang & Yushi Zhang & Hanyue Li & Meitong Ou & Yongkang Yu & Fan Zhang & Huijuan Yin & Zhuo Mao & Lin Mei, 2024. "Catalytic activity of violet phosphorus-based nanosystems and the role of metabolites in tumor therapy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42277-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.