Targeting the Gas6-TAM-SOCS1/3 axis: CP-25 attenuates macrophage dysfunction in primary Sjögren's syndrome

The etiology of primary Sjögren's syndrome (pSS) remains largely unexplained to date, and there is a relative lack of effective clinical treatment options.This study aimed to explore the potential therapeutic mechanism of paeoniflorin-6'-O-benzenesulfonate (CP-25) for pSS, especially regarding whether it exerts its effect by regulating the Gas6/TAM signaling axis. The study assessed the expression of the Gas6/TAM axis and its association with macrophage polarization using labial gland tissues, peripheral blood samples from patients with primary Sjögren's syndrome (pSS), and an experimental Sjögren's syndrome mouse model. In vitro, RAW264.7 cells and submandibular gland epithelial cells were employed to analyze changes in the TAM-SOCS1/3 axis, JAK1-STAT1 pathway, and polarization markers (iNOS, Arg1). ELISA was used to detect Gas6 secretion by SGECs, while flow cytometry and confocal microscopy evaluated macrophage function.Both primary Sjögren's syndrome patients and experimental Sjögren's syndrome mice showed dysregulation of the Gas6/TAM signaling pathway, which was closely linked to macrophage polarization imbalance.CP-25 alleviated ESS mouse symptoms by activating the TAM-SOCS1/3 axis, inhibiting the JAK1-STAT1 pathway, and promoting M2 macrophage polarization. In vitro experiments confirmed that CP-25 stimulated salivary gland epithelial cells (SGECs) to secrete Gas6 and reduced matrix metalloproteinase-9 (MMP-9) expression. Moreover, exogenous Gas6 promoted M2 polarization via TAM receptor activation; knockdown of the Mer receptor impaired macrophage phagocytic function. The study also indicated that MMP-9 may be involved in regulating TAM receptors on macrophages.In conclusion, CP-25 treats pSS by regulating SGEC Gas6/MMP-9 secretion, targeting macrophage TAM-SOCS1/3, modulating JAK1-STAT1, and restoring macrophage function.