# ANGPTL2 inhibits macrophage pyroptosis and alleviates rheumatoid arthritis progression by regulating mitophagy via IGFBP5

## TL;DR

ANGPTL2 helps prevent joint damage in rheumatoid arthritis by controlling macrophage cell death and mitochondrial health through IGFBP5.

## Contribution

This study reveals ANGPTL2 as a novel regulator of mitophagy and pyroptosis in rheumatoid arthritis.

## Key findings

- ANGPTL2 deficiency worsens joint inflammation and bone erosion in collagen-induced arthritis.
- ANGPTL2 regulates mitophagy via IGFBP5 to suppress macrophage pyroptosis and NLRP3 inflammasome activation.
- AAV-Angptl2 treatment restores mitophagy and alleviates rheumatoid arthritis pathology in mice.

## 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.

Schematic diagram of the mechanism of ANGPTL2 in the treatment of rheumatoid arthritis.