Synovial CXCL3⁺FOSL2⁺ Macrophages Mediate Inflammation via FOSL2/AP-1 in Rheumatoid Arthritis: A Single-Cell...

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Macrophages are key players in rheumatoid arthritis (RA) pathogenesis, contributing to joint inflammation and bone destruction.
• The precise roles of activator protein-1 (AP-1) transcription factors in synovial macrophages during RA remain incompletely understood.

Purpose of the Study:

• To investigate the specific roles of individual AP-1 family members in regulating synovial macrophages in rheumatoid arthritis.
• To identify novel macrophage subsets and pathways involved in RA synovitis.

Main Methods:

• Analysis of two public single-cell transcriptomic datasets to profile synovial macrophages and identify AP-1 family members.
• Differential gene expression and gene set enrichment analyses to determine associated pathways.
• Intercellular communication analysis, bulk transcriptomic validation, and in vitro FOSL2 knockdown assays.

Main Results:

• Identification of JUND, FOSL2, and FOSB as highly enriched AP-1 members in the RA synovium.
• Discovery of a distinct CXCL3+FOSL2+ macrophage subset characterized by pro-inflammatory, metabolic, and differentiation pathways.
• Demonstration of FOSL2's role in promoting macrophage-driven inflammation and its interaction with endothelial cells via the FOSL2/AP-1 axis.

Conclusions:

• CXCL3+FOSL2+ macrophages are identified as key drivers of RA synovitis.
• The FOSL2/AP-1 axis represents a critical pathway regulating macrophage function in RA.
• Targeting the FOSL2/AP-1 axis in macrophages presents a promising therapeutic strategy for rheumatoid arthritis.