Acidosis Licenses the NLRP3 Inflammasome-Inhibiting Effects of Beta-Hydroxybutyrate and Short-Chain Carboxylic Acids

Abstract

NLRP3 inflammasome activation induces the cleavage and secretion of IL-1{beta} and IL-18, and causes pyroptosis. Generated during times of energetic crisis (e.g., caloric insufficiency), the ketone body {beta}-hydroxybutyrate (BHB) has been reported to inhibit NLRP3 inflammasome activation. However, the conditions under which BHB exerts this activity and whether other short-chain carboxylic acids (SCCAs) share this effect are unexplored. Since BHB is often produced in high abundance endogenously accompanied by metabolic acidosis, we aimed to examine the pH-dependence for the ability of BHB and similar molecules to inhibit NLRP3 inflammasome activation and to test receptors conferring these effects. Whereas {beta}-hydroxybutyric acid (BHBA) enantiomers function equivalently to dose-dependently inhibit NLRP3 inflammasome-induced IL-1{beta} secretion, sodium-{beta}-hydroxybutyrate (NaBHB) and NaOH-neutralized BHBA do not inhibit NLRP3 inflammasome activation. Acidifying the pH of the NaBHB stock solution or the media in which cells are exposed to NaBHB, or allowing the cells to endogenously acidify their media, enables NaBHB to inhibit NLRP3 inflammasome activation. Several other SCCAs also inhibit NLRP3 inflammasome activation in a pH-dependent manner and prevent pyroptotic cell death. Finally, Free Fatty Acid Receptor 3 (GPR41/FFAR3) activation phenocopies and augments the NLRP3 inflammasome-inhibiting effects of BHBA. In conclusion, acidification licenses the ability of BHB and related SCCAs to inhibit NLRP3 inflammasome activation, in part through GPR41/FFAR3, thereby expanding the repertoire of metabolites capable of modulating this important pro-inflammatory pathway during times of energetic crisis and optimizing conditions for the potential use of ketone bodies as anti-inflammatories. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/650510v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@f3b90corg.highwire.dtl.DTLVardef@f9fab5org.highwire.dtl.DTLVardef@1babd12org.highwire.dtl.DTLVardef@d30d88_HPS_FORMAT_FIGEXP M_FIG C_FIG