Stanniocalcin-1 drives pro-inflammatory macrophage polarization and sustains chronic inflammation in rheumatoid...

To define how stanniocalcin-1 (STC1) shapes macrophage polarization and chronic inflammation in rheumatoid arthritis (RA).

We integrated bulk and single-cell transcriptomes from RA synovium, performed functional assays after STC1 gain- and loss-of-function in RAW264.7 cells, and evaluated disease phenotypes in a CIA model with STC1 knockdown. Single-cell clusters were annotated by canonical markers and reference mapping (SingleR/CellMarker/Azimuth), with targeted validation of the STC1-high subset. We further correlated STC1 with oxidative-stress pathways and prespecified signaling pathway (NF-κB/STAT1/MAPK).

STC1 expression in RA synovia was correlated with an immunosuppressive gene profile (reduced MHC antigen presentation and chemokine expression) alongside upregulation of innate inflammatory and oxidative stress regulators (e.g., IRAK1, TRAF6, TAK1). Single-cell analysis revealed STC1 was predominantly expressed by a pro-fibrotic macrophage subset induced by IL-4/Dex/TGFβ in RA, suggesting STC1 marks a distinct macrophage phenotype involved in tissue remodeling. In vitro, knocking down STC1 reduced migration and invasion phenotype while overexpression STC1 produced inverse influences. In addition, STC1 skewed macrophage differentiation toward a pro-inflammatory M1 state: STC1-overexpressing macrophages showed increased M1 markers and cytokines, while M2 marker expression was dampened. Conversely, STC1 silencing enhanced M2 polarization. In the CIA model, mice with STC1 knockdown exhibited reduced arthritis severity, evidenced by decreased joint swelling and inflammatory cell infiltration. These mice had significantly lower IL-6 levels in affected joints and an increased ratio of M2 macrophages, indicating a shift toward an anti-inflammatory milieu.

Our study delineates the significant role of STC1 in RA, emphasizing its influence on macrophage polarization and chronic inflammation. Elevated STC1 expression in RA synovia correlates with an immunosuppressive gene profile and heightened innate inflammatory pathways. STC1 promotes M1 macrophage polarization while attenuating M2 differentiation, exacerbating joint inflammation in a collagen-induced arthritis model. These findings highlighted STC1 as a potential biomarker for RA severity and highlight its mechanistic involvement in disease pathogenesis.