CCL7 promotes macrophage polarization and synovitis to exacerbate rheumatoid arthritis
Chemokine C-C motif ligand 7 (CCL7) is implicated in various immune and inflammatory processes; however, its role in rheumatoid arthritis (RA) remains unclear. In this study, we observed that CCL7 expression was upregulated in synovial M1-polarized macrophages and in the serum of RA mice and patients. CCL7 was found to promote macrophage polarization toward the M1 phenotype while inhibiting M2 differentiation <i>in vitro</i>. Furthermore, intra-articular injection of recombinant CCL7 protein in mice resulted in enhanced M1 polarization, increased inflammation, and fibrosis within synovial tissues, which exacerbated arthritis-associated pain. These effects were partially mitigated by treatment with a CCL7 neutralizing antibody. Mechanistically, we identified a CCL7 autocrine positive feedback loop that amplifies inflammation via the CCL7-CCR1-JAK2/STAT1 pathway. Collectively, our findings reveal a previously unrecognized CCL7-mediated autocrine inflammatory amplification loop that modulates macrophage polarization and exacerbates RA progression, positioning CCL7 as a potential therapeutic target for RA.
Authors
- Tianyu Chen (ORCID: https://orcid.org/0000-0001-7056-2947)
- Shuo Shi (ORCID: https://orcid.org/0000-0003-4387-3445)
- Changhai Ding (ORCID: https://orcid.org/0000-0002-9479-730X)
- Ru Feng (ORCID: https://orcid.org/0000-0003-4585-554X)
- Wenquan Liang (ORCID: https://orcid.org/0000-0001-5211-8148)
- Ke Hu (ORCID: https://orcid.org/0000-0003-1079-5137)
- Shuiyuan Chen (ORCID: https://orcid.org/0000-0001-9283-689X)
- Rongkai Zhang
- Xiaojia Li (ORCID: https://orcid.org/0000-0002-7833-3775)
- Yicheng Li (ORCID: https://orcid.org/0000-0003-4431-0003)
- Gang Liu (ORCID: https://orcid.org/0000-0001-8223-9880)
- Feng Gao (ORCID: https://orcid.org/0000-0002-7822-4317)
- Xiaoshuai Wang (ORCID: https://orcid.org/0000-0002-3895-1384)
- Xu Zhu (ORCID: https://orcid.org/0009-0003-8647-1320)
- Jun Chen
Institutions
- Hebei Medical University (CN)
- Hubei University of Medicine (CN)
- Anhui Medical University (CN)
- Third Hospital of Hebei Medical University (CN)
- Third Affiliated Hospital of Southern Medical University (CN)
- Nanfang Hospital (CN)
- Taihe Hospital (CN)
- Zhujiang Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- iScience
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1016/j.isci.2025.112177
- Citations
- 4
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Innovative Research Group Project of the National Natural Science Foundation of China
- National Natural Science Foundation of China
- Natural Science Foundation of Hebei Province
- Southern Medical University