Procyanidin B2 3,3''-di-O-gallate ameliorates imiquimod-induced skin inflammation by suppressing TLR7 signaling through the inhibition of endosomal acidification in dendritic cells

Abstract

The excessive activation of abnormal T helper 17 (Th17) cells and dendritic cells (DCs) in the dermis and epidermis causes severe inflammation of the skin. Toll-like receptor 7 (TLR7)-located in the endosomes of DCs-recognizes nucleic acids from pathogens as well as imiquimod (IMQ), which plays a crucial role in the pathogenesis of skin inflammation. Procyanidin B2 3,3''-di-O-gallate (PCB2DG), a polyphenol, has been reported to suppress the excessive production of proinflammatory cytokines from T cells. The aim of this study was to demonstrate the inhibitory effect of PCB2DG on skin inflammation and TLR7 signaling in DCs. In vivo studies showed that the clinical symptoms of dermatitis were markedly improved by the oral administration of PCB2DG in mouse dermatitis model caused by IMQ application, accompanied by the suppression of excessive cytokine secretion in the inflamed skin and spleen. In vitro, PCB2DG significantly decreased cytokine production in TLR7- or TLR9 ligand-stimulated bone marrow-derived dendritic cells (BMDCs), suggesting that PCB2DG suppresses endosomal toll-like receptors (TLR) signaling in DCs. The activity of endosomal TLRs depends on endosomal acidification, which was significantly inhibited by PCB2DG in BMDCs. The addition of cAMP, an accelerator of endosomal acidification, abrogated the inhibitory effect of cytokine production by PCB2DG. These results provide a new insight into developing functional foods, including PCB2DG, to improve the symptoms of skin inflammation through the suppression of TLR7 signaling in DCs.

Keywords: Endosomal acidification; Imiquimod; Procyanidin B2 gallate; TLR7.