Chen Ruiying, Zhang Xiaomeng, Li Bin, Tonetti Maurizio S, Yang Yijie, Li Yuan, Liu Beilei, Qian Shujiao, Gu Yingxin, Wang Qingwen, Mao Kairui, Cheng Hao, Lai Hongchang, Shi Junyu
Department of Oral and Maxillofacial Implantology, Shanghai PerioImplant Innovation Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Clin Invest. 2024 Nov 7;135(2):e180679. doi: 10.1172/JCI180679.
Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Tregs are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and a mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Tregs from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Tregs supported the accumulation and osteogenic differentiation of SSCs and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression levels of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Tregs, which bound to the Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg signaling to enhance bone repair and regeneration.
局部免疫炎症事件指导骨骼干细胞（SSCs）在损伤后修复/再生骨骼，但其机制尚未完全明确。我们推测，特定的调节性T细胞（Tregs）对于骨骼修复是必需的，并且通过器官特异性信号直接与SSCs相互作用。在骨折的人类患者和骨损伤小鼠模型中，我们均鉴定出了一种对骨损伤有反应的Treg亚群，其具有以CCR8为特征的骨修复能力。CCL1的局部产生诱导CCR8+ Tregs从外周大量迁移至损伤部位。根据颗粒蛋白（PGRN）（一种由颗粒蛋白（Grn）基因编码的蛋白质）的分泌情况，CCR8+ Tregs支持SSCs的聚集和成骨分化，从而促进骨骼修复。从机制上讲，我们发现CCL1增强了CCR8+ Tregs中碱性亮氨酸拉链ATF样转录因子（BATF）的表达水平，BATF与Grn启动子结合，增加Grn的翻译产量，进而增加PGRN的分泌。总之，我们的研究为骨免疫学提供了新的视角，并突出了操纵Treg信号以增强骨骼修复和再生的可能途径。
