Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1β production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1β-dependent inflammation. [Display omitted] •HDAC3 promotes IL-1β-dependent inflammation•HDAC3 restricts fatty acid oxidation for optimal NLRP3 inflammasome activation•HDAC3 translocates to mitochondria upon NLRP3 inflammasome activation•HDAC3 deacetylates HADHA at lysine 303 to restrain its enzyme activity Mitochondrial adaptations have been intimately linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Chi et al. show that HDAC3 translocates to mitochondria to deacetylate the FAO enzyme HADHA for optimal NLRP3 inflammasome activation.