4-1BBL suppresses the induction of anti-inflammatory responses by regulating the metabolic reprogramming of macrophages

Integration of intracellular signaling and metabolic reprogramming is critical for macrophage polarization and the induction of pro- or anti-inflammatory responses. However, the molecular switches that govern macrophage polarization remain incompletely defined. While 4-1BB ligand (4-1BBL), a member of the TNF superfamily, is known to promote sustained pro-inflammatory responses in macrophages, its role in anti-inflammatory macrophage responses has not been elucidated. This study identifies 4-1BBL plays a role as a negative regulator of anti-inflammatory macrophage polarization. Genetic deletion or pharmacological inhibition of 4-1BBL significantly enhanced the expression of anti-inflammatory cytokines and markers in mouse macrophages. In IL-4R signaling, 4-1BBL restrained JAK1 (Janus kinase 1) and STAT (signal transducer and activator of transcription) 6 phosphorylation, thereby modulating transcriptional programs associated with anti-inflammatory macrophage activation. Consistently, 4-1BBL deficiency elevated mitochondrial oxidative phosphorylation and fatty acid oxidation, accompanied by increased expression of metabolic genes in anti-inflammatory macrophages. Transcriptomic analysis further revealed a shift toward anti-inflammatory and oxidative metabolic gene signatures in IL-4-treated 4-1BBL-deficient macrophages. Importantly, inhibition of 4-1BBL signaling also augmented anti-inflammatory responses in human monocytes and facilitated the transition from pro-inflammatory to anti-inflammatory phenotypes. Collectively, these findings establish 4-1BBL as a molecular switch that regulates macrophage polarization by integrating inflammatory signaling with metabolic reprogramming, highlighting 4-1BBL as a potential therapeutic target for promoting inflammation resolution.