Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Division of Pediatric and Public Health, Adams School of Dentistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Cell. 2024 Jul 11;187(14):3690-3711.e19. doi: 10.1016/j.cell.2024.05.003. Epub 2024 Jun 4.
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 Dnmt3a 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.
不确定潜能的克隆性造血（CHIP）源自与年龄相关的造血祖细胞获得性突变，这些突变表现出克隆性扩张，并产生表型改变的白细胞。我们将 CHIP-DNMT3A 突变与 4946 名社区居住的成年人中牙周炎和牙龈炎症的更高患病率相关联。为了模拟 DNMT3A 驱动的 CHIP，我们使用具有杂合功能丧失突变 R878H 的小鼠，相当于人类热点突变 R882H。部分移植 Dnmt3a 骨髓（BM）细胞导致突变细胞在骨髓中向髓系和淋巴系的克隆性扩张，并在外周的 BM 和破骨细胞生成巨噬细胞中产生破骨细胞前体的升高丰度。受体小鼠中的 DNMT3A 驱动的克隆性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，与增强的破骨细胞生成、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 驱动的克隆性造血和随后的牙周炎。DNMT3A 驱动的 CHIP 代表一种可治疗的适应性造血不良状态，促进炎症性骨丢失。
