Extracellular HMGB1 impairs macrophage phagocytosis and promotes salivary gland dysfunction in Sjogren’s syndrome

Impaired phagocytosis of macrophages was observed in the salivary glands (SGs) of Sjogren's syndrome (SS). This study aims to investigate the dynamic changes of extracellular high mobility group box 1 (HMGB1) within these tissue microenvironments and its roles in macrophage function and subsequent gland dysfunction in SS. Our study detected a gradual increase in the expression and extracellular translocation of HMGB1 in the SGs of SS. Notably, this increased HMGB1 expression was negatively correlated with saliva associated AQP5 expression. Furthermore, elevated macrophages predominantly located around the duct, acinar, and infiltrate foci within the SGs expressed Toll-like receptor 4 and showed an M1 phenotype. Recombinant HMGB1 stimulation resulted in increased expression of major histocompatibility complex class II and a reduced phagocytic capacity of macrophages in vitro. Moreover, treatment with glycyrrhizin, a natural HMGB1 inhibitor, led to a significant improvement of saliva flow rates and a reduction of inflammatory cell infiltration and autoantibody levels when compared with phosphate-buffered saline-treated SS-like NOD/ShiLtJ mice. Our findings demonstrate that extracellular HMGB1 exacerbates the inflammatory-autoimmune microenvironments in SGs, suggesting that glycyrrhizin treatment may serve as a promising natural inhibitor for the management of SS.