10,11-Dehydrocurvularin attenuates LPS-induced neuroinflammation in BV2 cells by inhibiting the TLR2/MyD88/NLRP3 signaling pathway

Neuroinflammation, driven by microglial activation and Toll-like receptor 2 (TLR2) signaling, is a hallmark of neurodegenerative diseases. While 10,11-Dehydrocurvularin (DCV) is known for its anti-inflammatory properties, its specific effects on neuroinflammation remain poorly understood. This study evaluated DCV in lipopolysaccharide (LPS)-stimulated BV2 microglia. Nitric oxide (NO) was measured via the Griess assay, interleukin-1β (IL-1β) and IL-6 levels were quantified using ELISA or RT-qPCR, and the TLR2/MyD88/NLRP3 pathway was analyzed via Western blotting. To validate the target specificity, we employed a TLR2 agonist (Pam3CSK4), a pharmacological inhibitor (C29), and siRNA-mediated knockdown. Results showed that DCV concentration-dependently inhibited LPS-induced NO production (IC 50 = 3.501 μM) and significantly reduced IL-1β and IL-6 at both transcriptional and translational levels. Mechanistically, DCV suppressed the LPS-induced upregulation of TLR2, MyD88, and activation of the NLRP3 inflammasome. Notably, the TLR2 agonist Pam3CSK4 reversed the inhibitory effects of DCV on downstream inflammatory mediators. Conversely, the anti-inflammatory effect of DCV was occluded by TLR2 inhibition; neither pharmacological inhibition (C29) nor genetic knockdown (siRNA) of TLR2 allowed DCV to further reduce NO levels, indicating that DCV acts through a TLR2-dependent pathway. Transcriptomics profiling further revealed that DCV modulated immune-related genes, enriching the cytokine-cytokine receptor interaction and chemokine signaling pathways. Collectively, these findings demonstrate that DCV exhibits potent anti-neuroinflammatory activity by suppressing the TLR2/MyD88/NLRP3 signaling pathway, suggesting its potential as a promising lead compound for neuroinflammation-associated neurodegenerative diseases.