Targeting the PD-1-FABP5 Axis Modulates Adipose Tissue ILC2 Metabolism in Obesity

Obesity, intricately linked to metabolic disorders and chronic inflammation, demands targeted interventions. ILC2s, vital for adipose tissue energy homeostasis, emerge as promising candidates for obesity management. Our study reveals a notable surge in PD-1 expression within ILC2s from obese adipose tissue, leading to an exhausted phenotype with diminished cytokine production and proliferation. Elevated osteopontin (OPN) in adipose tissue correlates with increased PD-1 expression in ILC2s. Adipocytes, primary PD-L1 sources, interact with ILC2-expressed PD-1, impairing functionality. The PD-1 cascade induces metabolic shifts in ILC2s, influencing fatty acid uptake and energy metabolism modulation. PD-1: PD-L1 signaling negatively regulates fatty acid binding protein (FABP) 5. Inhibiting FABP5 suppresses cytokine production in ILC2s, attenuating their anti-obesity effects. Observations extend to human adipose tissue, revealing a conserved OPN-PD-1 axis. Together, our findings elucidate the OPN-driven PD-1 induction in adipose-resident ILC2s, highlighting intricate adipocyte-mediated PD-1: FABP5 axis effects on ILC2 metabolic adaptations in obesity.