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

Xuyang Xia, Chenjia He, Zhinan Xue, Yuelan Wang, Yun Qin, Zhixiang Ren, Yupeng Huang, Han Luo, Hai-Ning Chen, Wei-Han Zhang, Li-Bin Huang, Yunying Shi, Yangjuan Bai, Bei Cai, Lanlan Wang, Feng Zhang, Maoxiang Qian, Wei Zhang, Yang Shu, Geng Yin (), Heng Xu () and Qibing Xie ()
Additional contact information
Xuyang Xia: Sichuan University
Chenjia He: Sichuan University
Zhinan Xue: Sichuan University
Yuelan Wang: Sichuan University
Yun Qin: Sichuan University
Zhixiang Ren: Sichuan University
Yupeng Huang: Sichuan University
Han Luo: Sichuan University
Hai-Ning Chen: Sichuan University
Wei-Han Zhang: Sichuan University
Li-Bin Huang: Sichuan University
Yunying Shi: Sichuan University
Yangjuan Bai: Sichuan University
Bei Cai: Sichuan University
Lanlan Wang: Sichuan University
Feng Zhang: Quzhou People’s Hospital
Maoxiang Qian: Children’s Hospital of Fudan University
Wei Zhang: Central South University
Yang Shu: Sichuan University
Geng Yin: Sichuan University
Heng Xu: Sichuan University
Qibing Xie: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57361-0

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