Abstract
A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, antitumor, anti-inflammatory, antibacterial, and neuroprotective activities. Although the anti-inflammatory function of SA has been reported, the effect of SA on the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has not been explored. In the present study, to elucidate the anti-inflammatory mechanism of SA, we examined whether SA modulates the NLRP3 inflammasome. We found that SA blocked caspase-1 activation and IL-1β secretion by inhibiting NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). Apoptosis-associated speck-like protein containing CARD (ASC) pyroptosome formation was consistently blocked by SA treatment. SA specifically inhibited NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. In addition, SA had no significant effect on the priming phase of the NLRP3 inflammasome, such as pro-IL-1β and NLRP3 inflammasome expression levels. Moreover, we found that SA attenuated IL-1β secretion in LPS-induced systemic inflammation in mice and reduced lethality from endotoxic shock. Our findings suggest that the natural compound SA has potential therapeutic value for the suppression of NLRP3 inflammasome-associated inflammatory diseases.
Highlights
Sinapic acid (SA, 3,5-dimethoxy-4-hydroxycinnamic acid) is a polyphenol compound commonly present in edible food plants such as wheat, rice, spices, oil seeds, citrus fruits, vegetables, and cereals [1]
We investigated the possibility that sinapic acid (SA) modulates the nucleotide-binding oligomerization (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and provide biochemical evidence that SA regulates inflammatory signaling by suppressing NLRP3 inflammasome activation in vitro and in vivo
We found that cell viability was not significantly altered by SA at concentrations up to 300 μM for 12 h (Figure 1B)
Summary
Sinapic acid (SA, 3,5-dimethoxy-4-hydroxycinnamic acid) is a polyphenol compound commonly present in edible food plants such as wheat, rice, spices, oil seeds, citrus fruits, vegetables, and cereals [1]. SA has GABAA receptor antagonistic properties and shows a neuroprotective effect on kainic acid (KA)-induced hippocampal brain damage in mice [9]. SA shows anti-inflammatory activities in the RAW 264.7 cell line by suppressing lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, and IL-1β production. The NLRP3 inflammasome has been extensively studied because it is activated by a wide range of signals derived from pathogens as well as hosts and has been linked to the pathogenesis of diverse human diseases [14,20]. NLRP3 and pro-IL-1β are transcriptionally upregulated by nuclear factor-κB (NF-κB) signaling in response to LPS-binding to Toll-like receptor 4 (TLR4) [21]. We investigated the possibility that SA modulates the NLRP3 inflammasome and provide biochemical evidence that SA regulates inflammatory signaling by suppressing NLRP3 inflammasome activation in vitro and in vivo
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