Ham Jongho, Koh Jaemoon, Kim Jungeun, Cho Joo-Youn, Kim TaeSoo, Chung Doo Hyun, Bae Yong-Soo, Kim Hye Young
Laboratory of Mucosal Immunology, Department of Biomedical and Sciences BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, South Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, South Korea; CIRNO, Sungkyunkwan University, Suwon 16419, South Korea.
Department of Pathology, Seoul National University College of Medicine, Seoul 03080, South Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.
Mol Ther. 2025 Apr 2;33(4):1842-1859. doi: 10.1016/j.ymthe.2025.02.015. Epub 2025 Feb 12.
Obesity is closely linked to metabolic dysregulation and chronic inflammation, which significantly impact immune cell functions in adipose tissue. Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of energy homeostasis, positioning them as promising targets for obesity management. However, the mechanisms governing ILC2 activity and their therapeutic potential in obesity are not fully understood. In this study, we demonstrate that ILC2s in obese adipose tissue exhibit increased PD-1 expression, leading to an exhausted phenotype with diminished cytokine production and proliferation. Elevated osteopontin (OPN) levels in adipose tissue are associated with higher PD-1 expression on ILC2s, while adipocyte-derived PD-L1 interacts with PD-1 to further impair ILC2 functionality. Importantly, blocking PD-1 signaling prevents weight gain and alleviates obesity-related metabolic dysfunctions. In addition, the adoptive transfer of PD-1-deficient ILC2s reduces diabetic phenotypes in obese models. Mechanistically, PD-1 signaling drives metabolic reprogramming in ILC2s, affecting fatty acid uptake and energy metabolism through the downregulation of fatty acid binding protein 5 (FABP5). These results, corroborated by findings in human adipose tissue, suggest a conserved OPN-PD-1 axis. Our study identifies the OPN-PD-1-FABP5 pathway as a crucial regulator of ILC2 function in adipose tissue and presents an emerging immune cell-based therapeutic target for obesity treatment.
肥胖与代谢失调和慢性炎症密切相关，这会显著影响脂肪组织中免疫细胞的功能。2型固有淋巴细胞（ILC2s）已成为能量稳态的关键调节因子，使其成为肥胖管理的有希望的靶点。然而，控制ILC2活性的机制及其在肥胖中的治疗潜力尚未完全了解。在本研究中，我们证明肥胖脂肪组织中的ILC2s表现出PD-1表达增加，导致细胞因子产生和增殖减少的耗竭表型。脂肪组织中骨桥蛋白（OPN）水平升高与ILC2s上较高的PD-1表达相关，而脂肪细胞衍生的PD-L1与PD-1相互作用以进一步损害ILC2功能。重要的是，阻断PD-1信号传导可防止体重增加并减轻肥胖相关的代谢功能障碍。此外，过继转移缺乏PD-1的ILC2s可减轻肥胖模型中的糖尿病表型。从机制上讲，PD-1信号传导驱动ILC2s中的代谢重编程，通过下调脂肪酸结合蛋白5（FABP5）影响脂肪酸摄取和能量代谢。这些结果得到人类脂肪组织研究结果的证实，表明存在保守的OPN-PD-1轴。我们的研究确定OPN-PD-1-FABP5途径是脂肪组织中ILC2功能的关键调节因子，并提出了一种新兴的基于免疫细胞的肥胖治疗靶点。
