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Updated: Mar 14, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
ANGPTL2 inhibits macrophage pyroptosis and alleviates rheumatoid arthritis progression by regulating mitophagy via
Yuqi Liu1, Qiudong Yang1, Zhendong Huang1
1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Abstract:
Dysregulated macrophage pyroptosis and impaired mitophagy have emerged as critical drivers of rheumatoid arthritis (RA) progression, yet their upstream regulatory mechanisms remain unclear. Previous studies have demonstrated that ANGPTL2 deficiency aggravates alveolar bone loss in periodontitis, a condition that shares mechanistic similarities with RA in terms of bone destruction. Given the established link between periodontitis and RA, these findings suggest that ANGPTL2 may also play a protective role in RA-related joint pathology. In this study, we demonstrate that ANGPTL2 deficiency worsens joint inflammation, bone erosion, and macrophage pyroptosis in mice with collagen-induced arthritis (CIA). Mechanistically, ANGPTL2 loss impairs mitophagy and promotes mitochondrial dysfunction by inhibiting IGFBP5, leading to sustained NLRP3 inflammasome activation. Intra-articular administration of AAV-Angptl2 restores mitophagy, suppresses pyroptosis, and alleviates RA pathology. These findings identify ANGPTL2 as a key regulator of macrophage mitophagy and suggest its therapeutic potential in RA. Schematic diagram of the mechanism of ANGPTL2 in the treatment of rheumatoid arthritis.
Insights
Angiopoietin-like 2 (ANGPTL2) protects against rheumatoid arthritis (RA) by enhancing macrophage mitophagy and suppressing pyroptosis. Restoring ANGPTL2 alleviates joint inflammation and bone erosion in RA models.
Area of Science:
- Immunology
- Rheumatology
- Cell Biology
Background:
- Rheumatoid arthritis (RA) progression is linked to macrophage pyroptosis and impaired mitophagy.
- ANGPTL2 deficiency exacerbates bone loss in periodontitis, suggesting a potential role in RA.
- The upstream regulators of these processes in RA remain largely unknown.
Purpose of the Study:
- To investigate the role of ANGPTL2 in rheumatoid arthritis (RA) pathogenesis.
- To elucidate the molecular mechanisms by which ANGPTL2 influences macrophage function and joint pathology in RA.
- To evaluate the therapeutic potential of ANGPTL2 in RA.
Main Methods:
- Collagen-induced arthritis (CIA) mouse model.
- Assessment of joint inflammation, bone erosion, and macrophage pyroptosis.
- Analysis of mitophagy, mitochondrial function, and NLRP3 inflammasome activation.
- Adeno-associated virus (AAV)-mediated gene delivery of Angptl2.
Main Results:
- ANGPTL2 deficiency aggravated joint inflammation, bone erosion, and macrophage pyroptosis in CIA mice.
- ANGPTL2 deficiency impaired mitophagy and promoted mitochondrial dysfunction by inhibiting IGFBP5, leading to NLRP3 inflammasome activation.
- Intra-articular AAV-Angptl2 administration restored mitophagy, suppressed pyroptosis, and alleviated RA pathology.
Conclusions:
- ANGPTL2 is a critical regulator of macrophage mitophagy and pyroptosis in the context of rheumatoid arthritis.
- ANGPTL2 deficiency exacerbates RA by impairing mitophagy and promoting NLRP3 inflammasome activation.
- ANGPTL2 represents a promising therapeutic target for rheumatoid arthritis.
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