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 () and Lihong Shi ()
Additional contact information
Jing Liang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yang Wan: Chinese Academy of Medical Sciences & Peking Union Medical College
Jie Gao: Chinese Academy of Medical Sciences & Peking Union Medical College
Lingyue Zheng: Chinese Academy of Medical Sciences & Peking Union Medical College
Jingwei Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Peng Wu: Chinese Academy of Medical Sciences & Peking Union Medical College
Yue Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Bingrui Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Ding Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yige Ma: Chinese Academy of Medical Sciences & Peking Union Medical College
Biao Shen: Chinese Academy of Medical Sciences & Peking Union Medical College
Xue Lv: Chinese Academy of Medical Sciences & Peking Union Medical College
Di Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
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
Jinhua Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
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
Hang Yin: Tsinghua University
Xiaofan Zhu: Chinese Academy of Medical Sciences & Peking Union Medical College
Lihong Shi: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50066-w

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