Tumor Necrosis Factor-Induced Neuropilin-2 in Fibroblast-Like Synoviocytes Exacerbates Rheumatoid Arthritis

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and destruction.
• Fibroblast-like synoviocytes (FLS) play a critical role in RA pathogenesis.
• Neuropilin-2 (NRP2) has been implicated in inflammatory processes, but its specific role in RA remains to be fully elucidated.

Purpose of the Study:

• To investigate the role of tumor necrosis factor (TNF)-induced neuropilin-2 (NRP2) in rheumatoid arthritis (RA).
• To explore the potential of NRP2 as a therapeutic target in RA fibroblast-like synoviocytes (FLS).

Main Methods:

• Quantification of NRP2 in serum and synovial fluid from healthy, osteoarthritis (OA), and RA patients.
• Analysis of NRP2 expression in synovial tissues.
• Generation of NRP2 knockout mice and evaluation in serum-transfer-induced arthritis (STIA) models.
• Assessment of NRP2's effect on FLS proliferation, apoptosis, and cytokine secretion.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to identify p65-binding sites in the NRP2 locus.

Main Results:

• Elevated NRP2 levels in RA serum correlated with disease activity.
• TNF upregulated NRP2 expression in FLS via the transcription factor p65.
• NRP2 amplified inflammation and tissue damage by increasing FLS proliferation and pro-inflammatory cytokine/chemokine/MMP release.
• NRP2 knockout alleviated joint inflammation and damage in STIA models.
• NRP2-mediated inflammation was primarily driven by FAPα+THY1+ cells.

Conclusions:

• TNF-induced NRP2 is a key driver of inflammatory persistence in RA.
• NRP2 serves as a promising diagnostic biomarker for RA.
• Targeting the TNF-p65-NRP2 axis in FLS presents a novel therapeutic strategy for RA.
• The FAPα+THY1+ cell subset is critical for NRP2-mediated inflammation in RA.