Macrophage-derived secretory Clusterin amplifies fibroblast-like synoviocyte activation through PI3K/AKT and NF-κB signaling in rheumatoid arthritis

Abstract

Secretory clusterin (sCLU) has been implicated in inflammatory diseases, yet its role in rheumatoid arthritis (RA) remains poorly defined. Here, we showed that serum sCLU levels were significantly elevated in patients with RA compared with healthy controls ( n = 192 RA; n = 139 HC) and were associated with disease activity. Receiver operating characteristic analysis demonstrated moderate diagnostic performance for RA discrimination (AUC = 0.783, 95% CI 0.730–0.837). Mechanistically, M1-polarized macrophages exhibited enhanced sCLU secretion, whereas RA fibroblast-like synoviocytes (RA-FLS) produced minimal sCLU, identifying inflammatory macrophages as an important source of extracellular sCLU. Using a Transwell co-culture system and recombinant sCLU stimulation, we found that sCLU amplified inflammatory cytokine production and promoted the proliferative, migratory, invasive, and apoptosis-resistant phenotypes of RA-FLS under inflammatory conditions. These effects were accompanied with activation of the PI3K/AKT and NF-κB pathways and were significantly attenuated by pharmacological inhibition of either pathway. Proteomic screening, surface plasmon resonance, and co-immunoprecipitation analyses identified fibronectin 1 (FN1) as a direct binding partner of sCLU although its functional contribution requires further investigation. Importantly, genetic deletion of sCLU alleviated disease severity in collagen-induced arthritis mice. Collectively, our findings identify macrophage-derived sCLU as an inflammatory amplifier in RA and suggest that targeting sCLU may represent a potential therapeutic strategy for inflammatory arthritis.

The authors' abstract, as published at the source. International Immunopharmacology, 2026 · DOI ↗