Naringenin suppresses Toll‐like receptor 2‐mediated inflammatory responses through inhibition of receptor clustering on lipid rafts

Toll-like receptors (TLRs) are important innate immune receptors that sometimes cause excessive inflammatory responses and a perpetuated inflammatory loop that can be involved in inflammatory and autoimmune diseases. TLR2 recognizes bacterial lipoproteins in association with TLR1 or TLR6, and triggers inflammatory responses through activation of the transcription factor NF-κB. Naringenin, a type of citrus flavonoid, has been shown to possess anti-inflammatory properties, but its detailed action against TLR2 remains to be fully elucidated. The present study was designed to determine whether naringenin affects the inflammatory responses triggered by TLR2. Naringenin inhibited proinflammatory cytokine production and attenuated NF-κB activation in cells stimulated with a synthetic triacylated-type lipopeptide known as a TLR2/TLR1 ligand, as well as a synthetic diacylated-type lipopeptide known as a TLR2/TLR6 ligand. Moreover, a similar inhibitory effect was observed in cells stimulated with a crude lipophilic fraction extracted from Staphylococcus aureus cell walls and in cells stimulated with S. aureus cells. Furthermore, we showed that such an effect is caused by inhibition of TLR2 clustering in lipid rafts on the cell membrane. These results suggest that naringenin suppresses the inflammatory responses induced by TLR2 signal transduction. Our findings indicate a novel anti-inflammatory property of naringenin, mediated through the regulation of cell surface TLR2 functioning.