Targeting microglial TLR3-NF-κB/MAPK and JAK/STAT Axis: PEITC as a suppressor of poly (I:C)-induced neuroinflammation

Central nervous system (CNS) inflammation triggered by viral infections plays a crucial role in the pathogenesis of various neurological diseases. Microglia, as the resident immune cells of the CNS, detect viral components via Toll-like receptors (TLRs) and activate downstream inflammatory signaling pathways, such as NF-κB and mitogen-activated protein kinase (MAPK), which trigger a cascade of pro-inflammatory cytokines. Excessive immune responses often lead to neuronal damage and neurodegeneration. Phenethyl isothiocyanate (PEITC) is a small molecule derived from plants; previous studies have indicated its potential to modulate TLR-related signaling pathways and to exert immunomodulatory effects. This study investigates whether PEITC can inhibit Poly (I:C)-induced microglial inflammatory responses and related signal transduction pathways. Thus, we first conducted cell experiments using BV2 mouse microglial cells. The results showed that Poly (I:C) stimulation significantly upregulated NO and various pro-inflammatory factors (e.g., TNF-α, IL-1β, IL-6). At the same time, PEITC pre-treatment effectively inhibited these factors and enhanced the expression of anti-inflammatory cytokines, such as IL-10 and IFN-γ. Protein and mRNA analysis revealed that PEITC could significantly suppress the activation of TLR3, TICAM-1, p65, JAK/STAT, and MAPK signaling, and promote TRAF3 expression. In subsequent animal experiments, we induced acute neuroinflammation in mice with Poly (I:C) and found that PEITC effectively alleviated cortical inflammation, reduced Iba1 expression, and guided microglia to switch from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. In summary, this study confirms that PEITC can modulate the microglial activation and neuroinflammation induced by viral-like stimuli and participates in the regulation of multiple immune-related signaling pathways. This provides a potential drug candidate and research foundation for developing therapeutic strategies for virus-infection-related neuroinflammatory diseases in the future.