CAIA model of WT mice and Saa-TKO mice
This study aims to determine whether elevated expression of serum amyloid A (SAA), found in rheumatoid arthritis (RA) patients, contributes to the pathogenesis of RA. Mice with genetic deletion of all three inducible SAA genes (Saa-TKO) and their wildtype littermates were used in a collagen antibody-induced arthritis (CAIA) model, in which gross and histological changes of knees and ankles were compared with their wildtype (WT) littermates. Deletion of the inducible SAA genes significantly reduced arthritis index and swollen joints in Saa-TKO mice, along with reduced expression of major inflammatory cytokines, the chemokine CXCL12 and its receptor CXCR4. Peripheral blood was collected from mice and humans for preparation of mononuclear cells. Increased Th1 and Th17 lymphocytes, together with splenomegaly and decreased Treg cells, were prominent in WT mice but attenuated in Saa-TKO undergoing CAIA. Administration of recombinant SAA to the Saa-TKO mice reversed these changes. SAA also elevated CXCL12 and CXCR4 expression in a co-culture model with RA-FLS and CD4+ T cells, prompting formation of a complex of SAA-CXCL12-CXCR4. These findings indicate that SAA plays an active role in RA pathogenesis. SAA works together with CXCL12-CXCR4 to exacerbate RA, and the SAA-CXCL12-CXCR4 axis may be a target for therapeutic intervention.