Histone Deacetylase 3 Couples Mitochondria To Drive Inflammation By Configuring Fatty Acid Oxidation In Macrophages

Immune cell function is crucially dependent on specific metabolic programs dictated by mitochondria,including the oxidation of nutrients,synthesis of macromolecules,and post-translational modifications.Mitochondrial fitness and dynamics have been intimately linked to acute and chronic inflammation,but the metabolic cues and precise mechanisms remain unclear.Here we reveal an essential role of macrophage expression of histone deacetylase 3(HDAC3)in shaping mitochondrial adaptations for IL-1? production through non-histone deacetylation.In vivo,HDAC3 promotes lipopolysaccharide-induced acute inflammation and high-fat-diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation.Mechanistically,HDAC3 configured lipid profile in stimulated macrophages and restricted the fatty acid oxidation(FAO)supported by exogenous fatty acids for mitochondria to acquire adaptations in fitness and dynamics.Intriguingly,rather than an epigenomic modulator within nucleus,HDAC3 translocated to mitochondria to deacetylate an important FAO enzyme,mitochondrial trifunctional enzyme subunit ?,on lysine 303 and inactivated it.Thus,HDAC3 may serve as a controlling node that tunes the balance between acquiring adaptations in mitochondrial dysfunctions and sustaining their fitness for IL-1?-dependent inflammation.