CA72-4 derived from synovial cells inhibits monosodium urate-induced macrophage M1 polarization by activating the TIGIT/SHP-1 axis through binding to Siglec-15.

Excessive M1 polarization of macrophages is a key driver of inflammatory processes in gout, while the regulatory mechanisms involved remain unclear. Herein, the role of carbohydrate antigen 72-4 (CA72-4), derived from human synovial cells (HFLS), in regulating macrophage M1 polarization during gout progression was investigated. PMA was used to induce differentiation of THP-1 cells into macrophages, and the macrophages were then treated with a conventional medium (CM), the CM was from Non-treated HFLS (NCM), or the CM from MSU-treated HFLS (MCM), and then incubated with MSU treatment for 24 h. Cell viability was assessed by CCK-8 assay. IL-1β, TGF-β1, and CA72-4 levels in the supernatant of macrophages were detected by ELISA. The interaction between CA72-4 and sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was analyzed by Co-IP assay. MSU-induced HFLS to secrete CA72-4, and CA72-4 derived from HFLS inhibited MSU-induced macrophage M1 polarization. Mechanistically, CA72-4 activated the TIGIT/SHP-1 signaling in macrophages by binding to Siglec-15 on macrophages. As expected, Siglec-15 knockdown weakened the activation effect of MCM on TIGIT/SHP-1 signaling and the inhibitory effect on macrophage M1 polarization. MSU stimulated HFLS to secrete CA72-4, and CA72-4 derived from HFLS suppressed MSU-induced macrophage M1 polarization by activating TIGIT/SHP-1 signaling through targeting Siglec-15.