PPARγ brakes cytosolic DNA-induced macrophage inflammation by super-enhancer metabolic reprogramming

Abstract

Cytoplasmic DNA sensing triggers intense innate immune responses that require tight regulation. PPAR{gamma} is a master metabolic regulator in macrophages, but its role in cytoplasmic DNA immunity remains unclear. Using poly(dA:dT) to mimic cytoplasmic DNA stimulation, we combined transcriptomics, epigenomics (PPAR{gamma}/H3K27ac ChIP-seq), and functional assays. Poly(dA:dT) induced a cytokine storm with MAPK activation and apoptosis/necrosis. PPAR{gamma} activation by rosiglitazone (RGZ) antagonized this response, reducing cell death and transcriptionally inhibiting MAPK genes (e.g., DUSP4/10). Mechanistically, PPAR{gamma} bound promoters/enhancers via PPRE motifs and distal intergenic regions, remodeling H3K27ac (reduced at inflammatory loci, increased at metabolic genes). RGZ induced de novo super-enhancers coupling PPAR metabolic programs (e.g., CPT2) with immune suppression by targeting TLR4, CEBPB, and PIM3. Thus, PPAR{gamma} acts as a brake in cytoplasmic DNA immunity, integrating metabolic reprogramming and inflammation suppression through a multi-level genomic/epigenetic program. This study highlights PPAR{gamma} as a key immune-metabolic integrator and therapeutic target for diseases driven by excessive cytoplasmic DNA sensing.