<scp>4‐1BBL</scp> Suppresses Anti‐Inflammatory Responses by Regulating Metabolic Reprogramming of Macrophages

Integration of intracellular signalling and metabolic reprogramming is critical for macrophage polarisation and the induction of pro- or anti-inflammatory responses. However, the molecular switches that govern these processes 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 fully elucidated. This study identifies that 4-1BBL serves as a negative regulator of anti-inflammatory macrophage polarisation. Genetic deletion or pharmacological inhibition of 4-1BBL significantly enhanced the expression of anti-inflammatory cytokines and markers in mouse macrophages. In IL-4R signalling, 4-1BBL restrained Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6) phosphorylation, thereby modulating transcriptional programmes 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 towards anti-inflammatory and oxidative metabolic gene signatures in IL-4-treated 4-1BBL-deficient macrophages. Importantly, the inhibition of 4-1BBL signalling 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 crucial molecular switch that regulates macrophage polarisation by integrating inflammatory signalling with metabolic reprogramming, highlighting 4-1BBL as a potential therapeutic target for promoting inflammation resolution.