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Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia

Author

Listed:
  • Jing Liang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Yang Wan

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science
    Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Jie Gao

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Lingyue Zheng

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Jingwei Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Peng Wu

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Yue Li

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Bingrui Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Ding Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Yige Ma

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Biao Shen

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Xue Lv

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Di Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Na An

    (Nankai University)

  • Xiaoli Ma

    (Chinese Academy of Sciences)

  • Guangfeng Geng

    (Nankai University)

  • Jingyuan Tong

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Jinhua Liu

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Guo Chen

    (Nankai University)

  • Meng Gao

    (Toll Biotech Co. Ltd.)

  • Ryo Kurita

    (RIKEN BioResource Center)

  • Yukio Nakamura

    (RIKEN BioResource Center)

  • Ping Zhu

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Hang Yin

    (Tsinghua University)

  • Xiaofan Zhu

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science
    Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Lihong Shi

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

Abstract

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19+/− HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.

Suggested Citation

  • Jing Liang & Yang Wan & Jie Gao & Lingyue Zheng & Jingwei Wang & Peng Wu & Yue Li & Bingrui Wang & Ding Wang & Yige Ma & Biao Shen & Xue Lv & Di Wang & Na An & Xiaoli Ma & Guangfeng Geng & Jingyuan To, 2024. "Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50066-w
    DOI: 10.1038/s41467-024-50066-w
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    References listed on IDEAS

    as
    1. Jinhua Liu & Yapu Li & Jingyuan Tong & Jie Gao & Qing Guo & Lingling Zhang & Bingrui Wang & Hui Zhao & Hongtao Wang & Erlie Jiang & Ryo Kurita & Yukio Nakamura & Osamu Tanabe & James Douglas Engel & E, 2018. "Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Deepti Talwar & Joris Messens & Tobias P. Dick, 2020. "A role for annexin A2 in scaffolding the peroxiredoxin 2–STAT3 redox relay complex," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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