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

Area of Science:

• Immunology
• Rheumatology
• Pharmacology

Background:

• Primary Sjögren's syndrome (pSS) lacks effective treatments and its etiology is unclear.
• The Gas6/TAM signaling axis and macrophage polarization are implicated in pSS pathogenesis.
• Understanding these pathways is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the therapeutic mechanism of paeoniflorin-6 omino-O-benzenesulfonate (CP-25) in pSS.
• To determine if CP-25 regulates the Gas6/TAM signaling axis and influences macrophage polarization.
• To explore the role of Gas6, MMP-9, and TAM receptors in pSS.

Main Methods:

• Analysis of Gas6/TAM axis expression and macrophage polarization in pSS patients and a mouse model.
• In vitro studies using RAW264.7 cells and salivary gland epithelial cells (SGECs).
• ELISA, flow cytometry, confocal microscopy, and gene knockdown techniques were employed.

Main Results:

• Dysregulation of the Gas6/TAM pathway and imbalanced macrophage polarization were observed in pSS.
• CP-25 alleviated pSS symptoms in mice by activating TAM-SOCS1/3, inhibiting JAK1-STAT1, and promoting M2 polarization.
• CP-25 stimulated Gas6 secretion and reduced MMP-9 in SGECs; Gas6 promoted M2 polarization, while Mer receptor knockdown impaired phagocytosis.

Conclusions:

• CP-25 demonstrates therapeutic potential for pSS by modulating the Gas6/TAM-SOCS1/3 axis and JAK1-STAT1 pathway.
• CP-25 restores macrophage function and promotes M2 polarization, offering a novel treatment avenue.
• The interplay between SGEC Gas6/MMP-9 secretion and macrophage TAM receptors is critical in pSS treatment.