Macrophage PD-1 protects against metabolic dysfunction via ULK1-dependent PD-1 phosphorylation by blocking FBXO38-mediated ubiquitination and IRE1a-mediated ER stress

Immune checkpoint inhibitor (ICI) therapies are associated with an increased risk of metabolic syndrome; the underlying mechanisms remain elusive. We show here that anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, leading to an augmented susceptibility of mice to high-fat diet (HFD)-induced obesity, and systemic metabolic disorders. Mechanistically, LPS activates Unc-51-like autophagy activating kinase 1 (ULK1) via Mechanistic target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1a (IRE1a) and attenuates IRE1a autophosphorylation to suppress ER stress-mediated inflammatory responses. Inhibition or IRE1a knockout alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 in the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 in protecting against ER stress-driven systemic inflammation may provide new rational for combating both ICI therapy- and HFD-induced metabolic diseases. Overall design: To investigate the role of macrophage PD-1 in regulating high-fat diet (HFD)-induced obesity and metabolic disorders, we established a mouse model with PD-1 depletion in macrophage by crossing PD-1fl/fl mice with Lyz2-Cre mice. Myeloid-specific PD-1 KO mice (PD-1fl/fl Lyz2-Cre) and their littermate controls (PD-1fl/fl) were fed on HFD for 16 weeks. Subsequently, gene expression profiling was performed using RNA-seq data derived from epididymal white adipose tissues (eWAT) of myeloid-specific PD-1 KO mice or littermate controls.