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Macrophage PD-1 protects against metabolic dysfunction via ULK1-dependent PD-1 phosphorylation by blocking FBXO38-mediated ubiquitination and IRE1α-mediated ER stress

ABSTRACT: 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 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress ER stress-mediated inflammatory responses. Inhibition or IRE1α 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE304734 | GEO | 2025/10/26

REPOSITORIES: GEO

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