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

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.