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

Macrophages play a central role in joint inflammation and bone destruction in rheumatoid arthritis (RA). While activator protein-1 (AP-1) transcription factors have been implicated in RA pathogenesis, the specific roles of individual AP-1 members in regulating synovial macrophages remain unclear. To...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 26; no. 19; p. 9718
Main Authors: Wu, Yiwei, Yang, Jinming, Chen, Mengke, Chen, Xiaoxiang, Cao, Shan
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 06.10.2025
Subjects:
Analysis
Arthritis
Arthritis, Rheumatoid - genetics
Arthritis, Rheumatoid - metabolism
Arthritis, Rheumatoid - pathology
Cells
Chemokines, CXC - genetics
Chemokines, CXC - metabolism
Cyclin-dependent kinases
DNA binding proteins
Endothelium
Fibroblasts
Fos-Related Antigen-2 - genetics
Fos-Related Antigen-2 - metabolism
Gene Expression Profiling
Genes
Humans
Inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Kinases
Lymphocytes
Macrophages
Macrophages - metabolism
Metabolism
Rheumatoid arthritis
Rheumatoid factor
Single-Cell Analysis - methods
Single-Cell Gene Expression Analysis
Synovial Membrane - metabolism
Synovial Membrane - pathology
Transcription Factor AP-1 - genetics
Transcription Factor AP-1 - metabolism
Transcriptome
U937 Cells
United States
macrophage
single-cell transcriptome
AP-1
rheumatoid arthritis
FOSL2
ISSN:1422-0067, 1661-6596, 1422-0067
Online Access:Get full text
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Summary:Macrophages play a central role in joint inflammation and bone destruction in rheumatoid arthritis (RA). While activator protein-1 (AP-1) transcription factors have been implicated in RA pathogenesis, the specific roles of individual AP-1 members in regulating synovial macrophages remain unclear. To address this, two public single-cell transcriptomic datasets were first analyzed to profile synovial macrophages, and then to identify AP-1 family members and associated pathways via differential expression and gene set enrichment analyses. JUND, FOSL2, and FOSB were found to be highly enriched in the RA synovium, and a distinct CXCL3+FOSL2+ macrophage subset was identified, characterized by pro-inflammatory, metabolic, and differentiation-related pathways. Intercellular communication analysis further revealed that this CXCL3+FOSL2+ macrophage subset interacted with ACKR1+ endothelial cells within the synovial microenvironment. Validation in a large-cohort bulk transcriptomic dataset, together with functional assays using in vitro FOSL2 knockdown in U937 cell lines, further confirmed FOSL2’s role in promoting macrophage-driven inflammation. Collectively, these findings indicate that CXCL3+FOSL2+ macrophages drive RA synovitis via the FOSL2/AP-1 axis, highlighting a potential therapeutic target.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms26199718