Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss

IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Journal of Chemical Theory and Computation 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
{"title":"Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss","authors":"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","doi":"10.1016/j.cell.2024.05.003","DOIUrl":null,"url":null,"abstract":"<p>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-<em>DNMT3A</em> 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 <em>Dnmt3a</em><sup>R878H/+</sup> 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.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"51 1","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Theory and Computation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2024.05.003","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
引用次数: 0

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

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Journal of Chemical Theory and Computation
Journal of Chemical Theory and Computation 化学-物理:原子、分子和化学物理
CiteScore
9.90
自引率
16.40%
发文量
568
审稿时长
1 months
期刊介绍: The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.
期刊最新文献
Linear Response pCCD-Based Methods: LR-pCCD and LR-pCCD+S Approaches for the Efficient and Reliable Modeling of Excited State Properties. Non-adiabatic Couplings in Surface Hopping with Tight Binding Density Functional Theory: The Case of Molecular Motors. Bayesian Approach for Computing Free Energy on Perturbation Graphs with Cycles. Deterministic and Faster GW Calculations with a Reduced Number of Valence States: O(N2 ln N) Scaling in the Plane-Waves Formalism. The Dynamic Diversity and Invariance of Ab Initio Water.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1