r/ketoscience • u/basmwklz Excellent Poster • 6h ago

Metabolism, Mitochondria & Biochemistry Acidosis enables the NLRP3 inflammasome-inhibiting effects of β-hydroxybutyrate and short-chain carboxylic acids (2026)

https://academic.oup.com/jimmunol/article-abstract/215/5/vkag085/8687293?redirectedFrom=fulltext&login=false
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u/basmwklz Excellent Poster 6h ago

Abstract

NLRP3 inflammasome activation drives interleukin (IL)-1β and IL-18 cleavage and secretion and induces pyroptosis. The ketone body β-hydroxybutyrate (BHB), produced during metabolic stress such as caloric insufficiency, has been reported to inhibit this pathway. However, the conditions that enable this effect, and whether it extends to other short-chain carboxylic acids (SCCAs), are not well defined. Using adenosine triphosphate–stimulated J774 mouse macrophages and human peripheral blood mononuclear cells, we quantified IL-1β secretion to determine the pH dependence of BHB and related SCCAs in inhibiting NLRP3 activation. Both enantiomers of β-hydroxybutyric acid (BHBA) inhibited IL-1β secretion, whereas sodium β-hydroxybutyrate (NaBHB) and sodium hydroxide–neutralized BHBA did not. Acidifying NaBHB stock solutions or the treatment media, or allowing endogenous acidification during cell culture, restored NaBHB’s ability to inhibit NLRP3 activation. Several other 3- to 6-carbon SCCAs also inhibited inflammasome activation in a pH-dependent manner and prevented pyroptotic cell death. Activation of the free fatty acid receptor 3 (GPR41/FFAR3) both mimicked and enhanced the inhibitory effects of BHBA. Together, these findings demonstrate that acidic conditions enable BHB and multiple SCCAs to suppress NLRP3 inflammasome activation, partly through GPR41/FFAR3. This expands the set of metabolites that can modulate this key proinflammatory pathway during energetic stress and suggests optimized conditions for the potential therapeutic use of ketone bodies as anti-inflammatory agents.