Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing
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.
Authors
- Junyu Shi (ORCID: https://orcid.org/0000-0002-8241-2572)
- Maurizio S. Tonetti (ORCID: https://orcid.org/0000-0002-2743-0137)
- Shujiao Qian (ORCID: https://orcid.org/0000-0002-9276-3819)
- Yijie Yang (ORCID: https://orcid.org/0000-0003-0245-2433)
- Beilei Liu (ORCID: https://orcid.org/0000-0002-6675-4054)
- Hao Cheng (ORCID: https://orcid.org/0000-0003-1360-6290)
- Kairui Mao (ORCID: https://orcid.org/0000-0003-2321-870X)
- Xiaomeng Zhang (ORCID: https://orcid.org/0000-0003-2504-8599)
- Yuan Li (ORCID: https://orcid.org/0000-0001-8712-2470)
- Qingwen Wang (ORCID: https://orcid.org/0000-0003-4303-8271)
- Ruiying Chen (ORCID: https://orcid.org/0000-0002-7176-6500)
- Bin Li (ORCID: https://orcid.org/0000-0002-7640-8884)
- Ying‐Xin Gu
- Hongchang Lai
Institutions
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Xiamen University (CN)
- Anhui Medical University (CN)
- Chinese Academy of Sciences (CN)
- Ruijin Hospital (CN)
- Shanghai Ninth People's Hospital (CN)
- Shanghai Pulmonary Hospital (CN)
- Peking University Shenzhen Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Shanghai Skin Disease Hospital (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1172/jci180679
- Citations
- 14
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- National Natural Science Foundation of China
- Shanghai Jiao Tong University
- School of Medicine, Shanghai Jiao Tong University