IL-33 links inflammation and bone remodeling in experimental spondyloarthritis and human joint biopsies

Abstract

Objective

To investigate the pathogenic role of IL-33 in spondyloarthritis (SpA) by analyzing its expression in both murine and human joint tissues and functionally assessing its impact on fibroblasts. The study evaluated synovial and entheseal biopsies from patients with SpA to explore the potential contribution of IL-33 to joint inflammation and tissue remodeling.

Methods

A spontaneous arthritis model (SpAD) in DBA/1 mice was used to assess IL-33 expression via histology, immunohistochemistry, transcriptomics, RT-qPCR, and western blot. Sacroiliac and tarsal biopsies from patients with SpA were also analyzed. Differential gene expression was checked, and pathway enrichment was performed using Ingenuity Pathway Analysis. Primary fibroblasts were isolated from the joints of the mice's front and rear limbs, transfected with siRNA targeting Il33, and evaluated by RT-qPCR and western blot for inflammatory (Tnf, Nfkb) and osteogenic (Wnt2, Bmp2) markers. Cell viability was assessed via MTT assay.

Results

IL-33 expression was elevated in murine and human SpA joints, with strong cartilage and subchondral bone localization. Transcriptomic data indicated upregulation of IL-33 signaling and enrichment of proinflammatory and fibrotic pathways. Silencing of Il33 in fibroblasts significantly reduced IL-33 protein levels and decreased Tnf and Wnt2 expression at both mRNA and protein levels, while Bmp2 reduction was observed only at the transcript level.

Conclusion

IL-33 contributes to joint inflammation and may regulate osteogenic pathways implicated in pathological bone formation. These findings support IL-33 as a potential dual-action therapeutic target in SpA.