Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate

Abstract

Short chain fatty acids (SCFAs), a family of gut microbial metabolites, have been reported to promote preservation of endothelial function and thereby exert anti-atherosclerotic action. However, the precise mechanism mediating this protective action of SCFAs remains unknown. The present study investigated the effects of SCFAs (acetate, propionate and butyrate) on the activation of Nod-like receptor pyrin domain 3 (Nlrp3) inflammasome in endothelial cells (ECs) and associated carotid neointima formation. Using a partial ligated carotid artery (PLCA) mouse model fed with the Western diet (WD), we found that butyrate significantly decreased Nlrp3 inflammasome formation and activation in the carotid arterial wall of wild type mice (Asc+/+), which was comparable to the effect of gene deletion of the adaptor protein apoptosis-associated speck-like protein gene (Asc-/-). Nevertheless, both acetate and propionate markedly enhanced the formation and activation of the Nlrp3 inflammasome as well as carotid neointima formation in the carotid arteries with PLCA in Asc+/+, but not Asc-/- mice. In cultured ECs (EOMA cells), butyrate was found to significantly decrease the formation and activation of Nlrp3 inflammasomes induced by 7-ketocholesterol (7-Ket) or cholesterol crystals (CHC), while acetate did not inhibit Nlrp3 inflammasome activation induced by either 7-Ket or CHC, but itself even activated Nlrp3 inflammsomes. Mechanistically, the inhibitory action of butyrate on the Nlrp3 inflammasome was attributed to a blockade of lipid raft redox signaling platforms to produce O2•- upon 7-Ket or CHC stimulations. These results indicate that SCFAs have differential effects on endothelial Nlrp3 inflammasome activation and associated carotid neointima formation.

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…Generally speaking, the activation of the NLRP3 inflammasome involves two steps ( Sutterwala et al, 2014 ; Shao et al, 2015 ; Wu et al, 2018a ; Yuan et al, 2018 ; Figure 1 ). In the first step, a priming signaling is triggered by certain PAMPs or DAMPs on Toll-like receptor 4 (TLR4), which leads to the activation of the NF-κB-mediated pathway.…”

The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

“…The anti-inflammatory activity of SCFAs has been also evaluated in vivo: in a partially ligated carotid artery (PLCA) mouse model of atherosclerosis, it has been found that butyrate repressed endothelial Nlrp3 (Nlr family pyrin domaincontaining 3) inflammasome activation in ECs, via redox signaling pathways, and prevented arterial neointima formation. On the contrary, acetate and propionate exerted minimal inhibitory effects on inflammasome activation and even seem to augment the arterial neointima formation in the PLCA model [117]. The antiatherosclerotic activity of SCFAs was also confirmed by a recent study by Chen and collaborators showing that SCFAs from pectin fermentation are able to inhibit intestinal cholesterol absorption, to decrease serum total and low-density lipoprotein cholesterol and to protect ApoE -/against diet-induced atherosclerosis [118].…”

“…SCFAs inhibit the production of proinflammatory cytokines and the recruitment of immune cells to ECs, mechanisms mediated by binding to the free fatty acid (FFA) receptor types 2 and 3 and G-protein-coupled receptor 109A (GPR109A) and by inhibiting intracellular activity of histone deacetylases (HDACs), enzymes which can regulate multiple molecular processes involved in atherogenesis [97,[113][114][115]. Recently, it has emerged that SCFAs inhibit LPS-and TNFα-induced endothelial expression of VCAM-1, through activation of GPR41/43, which are SCFA receptors expressed in ECs, and inhibition of HDAC activity [116,117]. The anti-inflammatory activity of SCFAs has been also evaluated in vivo: in a partially ligated carotid artery (PLCA) mouse model of atherosclerosis, it has been found that butyrate repressed endothelial Nlrp3 (Nlr family pyrin domaincontaining 3) inflammasome activation in ECs, via redox signaling pathways, and prevented arterial neointima formation.…”

Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling

“…However, oral supplementation of butyrate can reverse these changes and inhibit VSMC proliferation, migration, and cell cycle progression in a dose-dependent manner in vitro. Butyrate also inhibits superoxide production and consequent Nod-like receptor pyrin domain 3 (Nlrp3) inflammasome formation and activation, which is beneficial against vascular inflammation or intimal hyperplasia [126]. These studies suggest that the association of gut microbial composition with arterial remodelling could potentially occur through an inhibitory effect of butyrate on VSMCs [125].…”