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CCL7 promotes macrophage polarization and synovitis to exacerbate rheumatoid arthritis II

ABSTRACT: Macrophage polarization and synovitis play significant roles in rheumatoid arthritis (RA). Chemokines are involved almost throughout the entire pathology of synovitis. However, the interaction between chemokines and macrophage polarization in RA has been seldom reported. This study found that chemokine C-C motif ligand 7 (CCL7) secreted by polarized M1 macrophages enhances M1 polarization, creating a positive feedback loop and revealing the role of CCL7 in the progression of rheumatoid arthritis. In this research, RNA sequencing indicated that M1 polarized macrophages secrete a large amount of CCL7, which further enhances M1 polarization. Through immunohistochemistry and enzyme-linked immunosorbent assay, it was found that the expression of CCL7 in the synovial tissue and serum of RA patients and mice was upregulated. Intra-articular injection of CCL7 recombinant protein exacerbated M1 polarization of macrophages, inflammation, fibrosis in the synovial tissue, and worsened arthritis pain in mice, which was improved after the injection of CCL7 neutralizing antibody. In addition, CCL7 promoted M1 polarization of macrophages and reversed the M2 polarization induced by IL-4, and it also promoted macrophage proliferation and migration. Although it had an inhibitory effect on chondrocyte activity, it did not show a significant impact on chondrocyte metabolism. Mechanistically, CCL7 targets CCR1 to promote M1 polarization of macrophages, a process partly mediated through the activation of the JAK2/STAT1 pathway. When stimulated by CCL7, macrophages secreted a vast amount of pro-inflammatory factors, exacerbating synovitis and cartilage damage, leading to the aggravation of RA disease. Our research established a positive feedback loop between M1 polarization of macrophages and CCL7, indicating that blocking CCL7 could improve the progression of RA, suggesting CCL7 as a potential target for RA treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE285977 | GEO | 2025/01/08

REPOSITORIES: GEO

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Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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CCL7 promotes macrophage polarization and synovitis to exacerbate rheumatoid arthritis II

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