Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss

IF 45.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cell Pub Date : 2024-06-04 DOI:10.1016/j.cell.2024.05.003
Hui Wang, Kimon Divaris, Bohu Pan, Xiaofei Li, Jong-Hyung Lim, Gundappa Saha, Marko Barovic, Danai Giannakou, Jonathan M. Korostoff, Yu Bing, Souvik Sen, Kevin Moss, Di Wu, James D. Beck, Christie M. Ballantyne, Pradeep Natarajan, Kari E. North, Mihai G. Netea, Triantafyllos Chavakis, George Hajishengallis
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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Abstract Image

由突变的 DNMT3A 驱动的克隆造血促进了炎症性骨质流失
具有不确定潜能的克隆性造血(CHIP)是由造血祖细胞中与衰老相关的获得性突变引起的,它表现出克隆性扩增并产生表型改变的白细胞。在 4946 名居住在社区的成年人中,我们发现 CHIP-DNMT3A 突变与牙周炎和牙龈炎症的高发病率有关。为了建立 DNMT3A 驱动的 CHIP 模型,我们使用了杂合功能缺失突变 R878H(相当于人类热点突变 R882H)的小鼠。用 Dnmt3aR878H/+ 骨髓(BM)细胞进行部分移植会导致突变细胞克隆扩增到髓系和淋巴系,并导致 BM 中破骨细胞前体和外周破骨细胞巨噬细胞的丰度升高。受体小鼠中 DNMT3A 驱动的克隆造血促进了自然发生的牙周炎,并加重了实验诱导的牙周炎和关节炎,这与破骨细胞生成增强、IL-17 依赖性炎症和中性粒细胞反应以及调节性 T 细胞免疫抑制活性受损有关。雷帕霉素治疗抑制了 DNMT3A 驱动的克隆性造血以及随后的牙周炎。DNMT3A 驱动的 CHIP 代表了一种可治疗的促进炎性骨质流失的适应不良造血状态。
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来源期刊
Cell
Cell 生物-生化与分子生物学
CiteScore
110.00
自引率
0.80%
发文量
396
审稿时长
2 months
期刊介绍: Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.
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