Single cell immunoprofile of synovial fluid in rheumatoid arthritis with TNF/JAK inhibitor treatment

• Published in: Nature communications Vol. 16; no. 1; pp. 2152 - 23
• Main Authors: Xia, Xuyang, He, Chenjia, Xue, Zhinan, Wang, Yuelan, Qin, Yun, Ren, Zhixiang, Huang, Yupeng, Luo, Han, Chen, Hai-Ning, Zhang, Wei-Han, Huang, Li-Bin, Shi, Yunying, Bai, Yangjuan, Cai, Bei, Wang, Lanlan, Zhang, Feng, Qian, Maoxiang, Zhang, Wei, Shu, Yang, Yin, Geng, Xu, Heng, Xie, Qibing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 38/77; 45/47; 45/91; 631/208/514/1949; 631/250/1619/554/1898; 631/250/2502; 631/250/2504/342; 692/699/1670/498; 96/47; Adalimumab - pharmacology; Adalimumab - therapeutic use; Animal models; Animals; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Cell interactions; CXCL13 protein; Disease Models, Animal; Female; Gene expression; Gene sequencing; Humanities and Social Sciences; Humans; Immune system; Inflammation; Janus Kinase Inhibitors - pharmacology; Janus Kinase Inhibitors - therapeutic use; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Middle Aged; Monoclonal antibodies; multidisciplinary; Piperidines; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rheumatoid arthritis; Science; Science (multidisciplinary); Single-Cell Analysis - methods; Stat1 protein; Synovial fluid; Synovial Fluid - cytology; Synovial Fluid - drug effects; Synovial Fluid - immunology; Synoviocytes; Synoviocytes - drug effects; Synoviocytes - immunology; Synoviocytes - metabolism; Tumor Necrosis Factor Inhibitors - pharmacology; Tumor Necrosis Factor Inhibitors - therapeutic use; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-57361-0

Numerous patients with rheumatoid arthritis (RA) manifest severe syndromes, including elevated synovial fluid volumes (SF) with abundant immune cells, which can be controlled by TNF/JAK inhibitors. Here, we apply single-cell RNA sequencing (scRNA-seq) and subsequent validations in SF from RA patients. These analyses of synovial tissue show reduced density of SF-derived pathogenic cells (e.g., SPP1 + macrophages and CXCL13 + CD4 + T cells), altered gene expression (e.g., SPP1 and STAT1 ), molecular pathway changes (e.g., JAK/STAT), and cell-cell communications in drug-specific manners in samples from patients pre-/post-treated with adalimumab/tofacitinib. Particularly, SPP1 + macrophages exhibit pronounced communication with CXCL13 + CD4 + T cells, which are abolished after treatment and correlate with treatment efficacy. These pathogenic cell types alone or in combination can augment inflammation of fibroblast-like synoviocytes in vitro, while conditional Spp1 knocking-out reduces RA-related cytokine expression in collagen-induced arthritis mice models. Our study shows the functional role of SF-derived pathogenic cells in progression and drug-specific treatment outcomes in RA. Inflammatory immune cells are found in the synovial fluid of patients with rheumatoid arthritis (RA). Here the authors use scRNA sequencing of synovial fluid cells from RA patients before and after treatment with adalimumab/tofacitinib and find changes in inflammatory SPP1+ macrophages and explore the function of these cells in mouse models.