Related Experiment Video
Updated: May 22, 2025
Visualization of IL-22-expressing Lymphocytes Using Reporter Mice
Published on: January 25, 2017
IL-33-Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1-IGF2R Axis in Ankylosing
Wenjun Hao1,2, Siwen Chen1,2, Hua Chao1,2
1Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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.
Insights
This study reveals that TREM2-positive macrophages drive new bone formation in ankylosing spondylitis. Targeting IL-33 signaling offers a potential therapy to halt spinal ankylosis.
Area of Science:
- Immunology
- Orthopedics
- Cell Biology
Background:
- Ankylosing spondylitis (AS) causes disability through pathological new bone formation, lacking targeted therapies.
- Macrophages orchestrate inflammation and tissue remodeling, but their role in AS bone formation is understudied.
Purpose of the Study:
- To investigate the role of macrophages, specifically TREM2-positive macrophages, in pathological new bone formation in AS.
- To identify molecular pathways and therapeutic targets for inhibiting new bone formation in AS.
Main Methods:
- Utilized a collagen antibody-induced arthritis (CAIA) mouse model for AS.
- Employed macrophage depletion and Trem2 knockout strategies.
- Analyzed the role of CREG1, IL-33, and associated signaling pathways (IGF2R-PI3K-AKT, STAT6).
Main Results:
- TREM2-positive macrophages were abundant at sites of new bone formation.
- Macrophage depletion and Trem2 knockout significantly reduced new bone formation in the CAIA model.
- TREM2-positive macrophages secreted CREG1, promoting osteogenic differentiation of ligament-derived progenitor cells (LDPCs) via the CREG1-IGF2R-PI3K-AKT pathway.
- IL-33 induced TREM2-positive macrophage differentiation through STAT6 phosphorylation.
Conclusions:
- IL-33-induced TREM2-positive macrophages play a critical role in pathological new bone formation in AS.
- Targeting the identified signaling pathways (IL-33/STAT6, CREG1/IGF2R/PI3K/AKT) may offer therapeutic strategies for ankylosing spondylitis and spinal ankylosis.
