IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis
Abstract 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 lar...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202500952 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849470012394307584 |
|---|---|
| author | Wenjun Hao Siwen Chen Hua Chao Zihao Li Hao Yang Dongying Chen Sifang Li Shuai Zhang Jingyu Zhang Jianru Wang Zemin Li Xiang Li Zhongping Zhan Tangming Guan Yiwen Zhang Wende Li Hui Liu |
| author_facet | Wenjun Hao Siwen Chen Hua Chao Zihao Li Hao Yang Dongying Chen Sifang Li Shuai Zhang Jingyu Zhang Jianru Wang Zemin Li Xiang Li Zhongping Zhan Tangming Guan Yiwen Zhang Wende Li Hui Liu |
| author_sort | Wenjun Hao |
| collection | DOAJ |
| description | Abstract 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+ 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+ 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+ macrophage‐mediated pathological new bone formation. In addition, it is found that IL‐33 promoted TREM2+ 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+ macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS. |
| format | Article |
| id | doaj-art-5d299b3ce6fd45008dae50d5a19f2ecc |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-5d299b3ce6fd45008dae50d5a19f2ecc2025-08-20T03:25:16ZengWileyAdvanced Science2198-38442025-05-011218n/an/a10.1002/advs.202500952IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing SpondylitisWenjun Hao0Siwen Chen1Hua Chao2Zihao Li3Hao Yang4Dongying Chen5Sifang Li6Shuai Zhang7Jingyu Zhang8Jianru Wang9Zemin Li10Xiang Li11Zhongping Zhan12Tangming Guan13Yiwen Zhang14Wende Li15Hui Liu16Department of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaPediatric Orthopaedics Beijing Jishuitan Hospital Capital Medical University Beijing 102200 ChinaDepartment of Rheumatology and Immunology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaDepartment of Rheumatology and Immunology The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaGuangdong Laboratory Animals Monitoring Institute Guangdong Key Laboratory of Laboratory Animals Guangzhou 510000 ChinaInstitute of Human Virology Department of Pathogen Biology and Biosecurity Key Laboratory of Tropical Disease Control of Ministry of Education Zhongshan School of Medicine Sun Yat‐sen University Guangzhou 510080 ChinaGuangdong Laboratory Animals Monitoring Institute Guangdong Key Laboratory of Laboratory Animals Guangzhou 510000 ChinaDepartment of Spine Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 ChinaAbstract 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+ 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+ 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+ macrophage‐mediated pathological new bone formation. In addition, it is found that IL‐33 promoted TREM2+ 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+ macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.https://doi.org/10.1002/advs.202500952ankylosing spondylitisCREG1IL33pathological new bone formationTREM2+ macrophages |
| spellingShingle | Wenjun Hao Siwen Chen Hua Chao Zihao Li Hao Yang Dongying Chen Sifang Li Shuai Zhang Jingyu Zhang Jianru Wang Zemin Li Xiang Li Zhongping Zhan Tangming Guan Yiwen Zhang Wende Li Hui Liu IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis Advanced Science ankylosing spondylitis CREG1 IL33 pathological new bone formation TREM2+ macrophages |
| title | IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis |
| title_full | IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis |
| title_fullStr | IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis |
| title_full_unstemmed | IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis |
| title_short | IL‐33‐Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1‐IGF2R Axis in Ankylosing Spondylitis |
| title_sort | il 33 induced trem2 macrophages promote pathological new bone formation through creg1 igf2r axis in ankylosing spondylitis |
| topic | ankylosing spondylitis CREG1 IL33 pathological new bone formation TREM2+ macrophages |
| url | https://doi.org/10.1002/advs.202500952 |
| work_keys_str_mv | AT wenjunhao il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT siwenchen il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT huachao il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT zihaoli il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT haoyang il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT dongyingchen il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT sifangli il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT shuaizhang il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT jingyuzhang il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT jianruwang il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT zeminli il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT xiangli il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT zhongpingzhan il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT tangmingguan il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT yiwenzhang il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT wendeli il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis AT huiliu il33inducedtrem2macrophagespromotepathologicalnewboneformationthroughcreg1igf2raxisinankylosingspondylitis |