Syringic acid suppresses inflammation by upregulation of SOCS3

Suppressor of cytokine signalling 3 (SOCS3), a protein that inhibits inflammatory molecules in microglia. A plant-derived phenolic compound, Syringic acid (SA), selectively increased SOCS3 levels in N-9 mouse microglial cells in a dose- and time-dependent manner. Similar effects were also observed in mouse primary microglia and astrocytes. In Lipopolysaccharide (LPS)-stimulated N-9 cells, SOCS3 expression decreased, but after SA treatment (LPS + SA), both mRNA and protein levels of SOCS3 increased. At the same time, pro-inflammatory mediators such as Tumor Necrosis Factor alpha (TNFα), Interleukin-1 receptor, type I (IL1R1), Interleukin-1 beta (IL1β), and Inducible Nitric Oxide Synthase (iNOS) were suppressed, along with a reduction in intracellular Reactive Oxygen Species generation (ROS) in LPS + SA-treated N-9 cells. Additionally, the expression of phospho-CREB was enhanced in LPS + SA-treated N-9 cells compared to only LPS-stimulated cells. Following the SiRNA knockdown of cAMP response element-binding protein (CREB), the upregulation of SOCS3 by syringic acid was abolished. These results confirm the role of CREB in this process. The findings suggest that SA promotes CREB activation, leading to SOCS3 expression, which may have therapeutic potential in neuroinflammatory disorders.