Polyphenols differentially inhibit degranulation of distinct subsets of vesicles in mast cells by specific interaction with granule-type-dependent SNARE complexes

Abstract

Anti-allergic effects of dietary polyphenols were extensively studied in numerous allergic disease models, but the molecular mechanisms of anti-allergic effects by polyphenols remain poorly understood. In the present study, we show that the release of granular cargo molecules, contained in distinct subsets of granules of mast cells, is specifically mediated by two sets of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, and that various polyphenols differentially inhibit the formation of those SNARE complexes. Expression analysis of RBL-2H3 cells for 11 SNARE genes and a lipid mixing assay of 24 possible combinations of reconstituted SNAREs indicated that the only two active SNARE complexes involved in mast cell degranulation are Syn (syntaxin) 4/SNAP (23 kDa synaptosome-associated protein)-23/VAMP (vesicle-associated membrane protein) 2 and Syn4/SNAP-23/VAMP8. Various polyphenols selectively or commonly interfered with ternary complex formation of these two SNARE complexes, thereby stopping membrane fusion between granules and plasma membrane. This led to the differential effect of polyphenols on degranulation of three distinct subsets of granules. These results suggest the possibility that formation of a variety of SNARE complexes in numerous cell types is controlled by polyphenols which, in turn, might regulate corresponding membrane trafficking.

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…Alternatively, there may be differential inhibition of gene expression, involving the inhibition of nuclear transcription targets (NF-KB or STAT), compared with cytokine or chemokine protein secretion. Instead, mediator trafficking and secretion may involve inhibition of specific target proteins involved in vesicle fusion, such as soluble N-ethylmaleimide-sensitive factor attachment protein complexes (71,72).…”

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

“…A potential mechanism of selectivity of flavonoids, where luteolin was the best inhibitor of histamine and β-hex release, may be disruption of distinct MC vesicle secretion by interacting with granule-dependent SNARE complexes. 64 Interestingly, the beneficial action of cromolyn may also not to be selective for MC as it could be mediated through inhibition of sensory nerve endings, recently shown for a cromolyn containing skin cream. 27 Other studies have shown that cromolyn may stimulate afferent nerves in humans.…”

Intracellular trafficking and secretion of inflammatory cytokines

“…VAMP8 can control various stages of granule-mediated secretion. Mast cells undergo piecemeal degranulation, which is regulated through the VAMP8 and VAMP7 as R-SNAREs located on secretory granules and Stx4/SNAP23 on the cell surface [92,96,[98][99][100]. In pancreatic acinar cells VAMP8 regulates granule-to-granule, but not granule-to-surface, fusion during compound exocytosis, whether this is the case for mast cell is unclear [101].…”