Lactate acts as a metabolic brake on inflammation by repressing NLRP3 transcription via NF-κB inhibition

Activation of the NLRP3 inflammasomes couples glycolytic metabolism to IL-1β-driven inflammation, but how pathologically elevated lactate feeds back on this pathway is unclear.

Using real-time bioenergetic Seahorse XF analysis, epigenetic profiling, and molecular signaling assays, we investigated the regulatory role of lactate in mouse bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages.

Pathophysiological concentrations of lactate suppressed ASC speck formation, caspase-1 activation, and IL-1β secretion induced by ATP, nigericin, or monosodium urate crystals. This inhibition was associated with a reversible downregulation of NLRP3 expression, whereas ASC, pro-caspase-1, and pro-IL-1β levels remained unaffected. Mechanistically, this suppressive effect was independent of the GPR81 receptor and reactive oxygen species (ROS). Instead, lactate utilized the monocarboxylate transporter (MCT) axis to fundamentally reprogram cellular metabolism, leading to the coordinated suppression of aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). The resulting decline in cellular ATP levels impaired ATP-dependent NF-κB p65 phosphorylation and subsequent NLRP3 promoter activity. Notably, while lactate globally increased histone lactylation and acetylation-including localized enrichment at the NLRP3 promoter-these epigenetic shifts were insufficient to overcome the metabolic-driven repression of NF-κB-dependent transcription.

Our findings identify lactate as a metabolic negative-feedback signal that restrains NLRP3 transcriptional priming by disrupting metabolic fitness. This study clarifies how the lactate-MCT-ATP- NF-κB axis serves as a critical metabolic checkpoint to limit inflammasome-driven inflammation in metabolically stressed microenvironments.