2. Academic Validation
  3. Targeting CD161 inhibitory receptors enhances NK cell-mediated changes in synovial fibroblast function in rheumatoid arthritis

Targeting CD161 inhibitory receptors enhances NK cell-mediated changes in synovial fibroblast function in rheumatoid arthritis

  • Int Immunopharmacol. 2025 Sep 12:165:115528. doi: 10.1016/j.intimp.2025.115528.
Junqin Lu 1,  Jiale Song 2,  Hongwei Yu 1,  Guangxue Gu 1,  Haoyu Zhao 2,  Fei Song 3,  Wei Zhou 4,  Tao You 5,  Jian Zhou 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
  • 3 Department of Orthopedics, The 901st Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Hefei, Anhui 230031, China.
  • 4 Department of Stomatology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China. Electronic address: zhouwei1788@qq.com.
  • 5 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230031, China. Electronic address: youtao@ustc.edu.cn.
  • 6 Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China. Electronic address: drzhoujian2021@163.com.
PMID: 40945032 DOI: 10.1016/j.intimp.2025.115528
Abstract

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease that still lacks reliable biomarkers. The mechanistic role of CD161 as an inhibitory receptor in RA pathogenesis and its potential for predicting therapeutic responses require further investigation.

Methods: We combined RNA Sequencing (RNA-seq), single-cell RNA Sequencing (scRNA-seq), and clinical sample analyses to characterize the specific expression of CD161 in RA. We constructed a collagen-induced arthritis (CIA) model and injected NK cells into the joint cavity. Additionally, we stimulated fibroblast-like synoviocytes (FLS) with IFN-γ in vitro, followed by whole-genome Sequencing and in vitro cell co-culture assays, to explore the mechanism by which CD161 regulates FLS function.

Results: CD161 was specifically overexpressed in synovial NK cells from RA patients and negatively correlated with NK cell-derived IFN-γ. Using a CD56+ NK cell line with regulated CD161 expression, we demonstrated that intra-articular injection of these cells alleviated CIA synovitis severity to a certain extent. In vitro, IFN-γ stimulation of FLS followed by whole-genome Sequencing, combined with CD56+ NK cell-FLS co-culture experiments, revealed that CD161 inhibited the tumor-like properties of FLS, likely via mechanisms involving IFN-γ and the PI3K-AKT pathway.

Conclusion: CD161 is a potential biomarker for RA. Targeted inhibition of CD161 in NK cells alleviates synovial inflammation in RA, highlighting its therapeutic potential.

Keywords

CD161; Fibroblast; IFN-γ; NK cell; Rheumatoid arthritis.

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