IL‐33‐Induced TREM2<sup>+</sup> Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis
Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2<sup>+</sup> macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2<sup>+</sup> macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2<sup>+</sup> macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2<sup>+</sup> macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2<sup>+</sup> macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.
Authors
- Sifang Li (ORCID: https://orcid.org/0000-0002-9767-9640)
- Wenjun Hao (ORCID: https://orcid.org/0000-0002-9854-035X)
- Tangming Guan (ORCID: https://orcid.org/0000-0002-4617-8221)
- Zemin Li (ORCID: https://orcid.org/0000-0002-7878-6870)
- Siwen Chen (ORCID: https://orcid.org/0000-0003-2138-7737)
- Jianru Wang (ORCID: https://orcid.org/0000-0002-9747-0652)
- Dongying Chen (ORCID: https://orcid.org/0000-0003-0167-3285)
- Wende Li (ORCID: https://orcid.org/0000-0001-8302-6123)
- Shuai Zhang (ORCID: https://orcid.org/0000-0003-0272-0856)
- Jingyu Zhang (ORCID: https://orcid.org/0000-0002-5629-9246)
- Zihao Li (ORCID: https://orcid.org/0000-0002-4040-8188)
- Hui Liu (ORCID: https://orcid.org/0000-0003-0754-402X)
- Yiwen Zhang (ORCID: https://orcid.org/0000-0002-5232-0335)
- Xiang Li (ORCID: https://orcid.org/0000-0002-4869-7041)
- Hao Yang (ORCID: https://orcid.org/0009-0005-8623-8531)
- Zhongping Zhan (ORCID: https://orcid.org/0000-0003-1104-3826)
- Hua Chao
Institutions
- Sun Yat-sen University (CN)
- Capital Medical University (CN)
- Peking University (CN)
- Beijing Jishuitan Hospital (CN)
- Key Laboratory of Guangdong Province (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Guangdong Laboratory Animals Monitoring Institute (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1002/advs.202500952
- Citations
- 5
- Primary Topic
- Autoimmune and Inflammatory Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 8.85
Funders
- National Natural Science Foundation of China
- Guangdong Science and Technology Department
- National Key Research and Development Program of China