Ather, J. L. | Search bioRxiv

bioRxiv2025

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

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

immunology↗

bioRxiv2024

Novel preclinical model of human lung cancer cachexia

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell specific KrasG12D/+ (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/615385v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@66d87dorg.highwire.dtl.DTLVardef@f1cb4org.highwire.dtl.DTLVardef@2580f1org.highwire.dtl.DTLVardef@3463d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗