Nature Communications (Jul 2024)

Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia

  • 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 Tong,
  • Jinhua Liu,
  • Guo Chen,
  • Meng Gao,
  • Ryo Kurita,
  • Yukio Nakamura,
  • Ping Zhu,
  • Hang Yin,
  • Xiaofan Zhu,
  • Lihong Shi

DOI
https://doi.org/10.1038/s41467-024-50066-w
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 17

Abstract

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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.