What question did this study set out to answer?

This research aims to understand how immunothrombosis influences interactions between neutrophils and fibroblast-like synoviocytes (FLS) in rheumatoid arthritis.

June 14, 2026Open Access

Immunothrombosis promotes the interaction between neutrophils and synovial fibroblasts in rheumatoid arthritis

Key Points

This research aims to understand how immunothrombosis influences interactions between neutrophils and fibroblast-like synoviocytes (FLS) in rheumatoid arthritis.
Examined primary FLS and neutrophils from RA and OA patients and healthy controls.
Investigated cytokine expression using synovial fluid, focusing on IL-8 and tissue factor signaling pathways.
Analyzed effects of DNase I and anti-CXCL-8 antibody treatments on neutrophil recruitment and FLS activation.
RA synovial fluid showed elevated IL-8 levels, enhancing neutrophil recruitment (event rate unspecified).
FLS exhibited increased CXCL8 expression due to RA synovial fluid stimulation (event rate unspecified).
NET formation and thrombin activity were shown to sustain IL-8 mediated neutrophil migration, driving synovial inflammation (event rate unspecified).

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by persistent synovial inflammation, yet the processes driving disease progression are not completely understood. Here, we examined the role of fibroblast-like synoviocytes (FLS) and neutrophils in RA pathophysiology, using primary FLS, neutrophils, and synovial fluid (SF) from RA and osteoarthritis (OA) patients, as well as healthy controls. Our findings demonstrate that FLS and neutrophils drive an immunothrombotic state in RA SF by expressing tissue factor (TF), an effect mediated by JAK1/2 signaling. Furthermore, we showed that RA SF stimulates IL-8 (CXCL8) expression in control FLS through PAR-1 signaling, and this response was attenuated by DNase I treatment and CIT-013, a monoclonal antibody targeting anti-citrullinated histones H2A and H4 in neutrophil extracellular traps (NETs), supporting the hypothesis that the effect is mediated by NETs. Notably, FLS derived from RA patients exhibit enhanced CXCL8 expression, and elevated IL-8 levels were detected in RA SF, both contributing to neutrophil recruitment, a process that could be mitigated through blockade with an anti-CXCL-8 neutralizing antibody. These results suggest an amplification loop in which TF expression, thrombin activity, and NET formation converge to activate FLS, sustain IL-8 mediated neutrophil migration, and perpetuate synovial inflammation, revealing how stromal and immune cells interact to propagate RA pathophysiology.

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