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Mol. Ther., February 12, 2025 | https://doi.org/10.1016/j.ymthe.2025.02.015 Modulating the PD-1-FABP5 Axis in ILC2s to Regulate Adipose Tissue Metabolism in Obesity

Jongho Ham ^1,2,10, Jaemoon Koh ^3,4, Jungeun Kim ^5,6, Joo-Youn Cho ^5,6,7, TaeSoo Kim ⁸, Doo Hyun ⁶, Chung ^3,4, Yong-Soo Bae ^9,10, and Hye Young Kim ^1,2,8,10*

¹Laboratory of Mucosal Immunology, Department of Biomedical and Sciences BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Korea
²Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
³Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea
⁴Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
⁵Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea
⁶Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
⁷Kidney Research Institute, Seoul National University Medical Research Center, Seoul 03080, Korea
⁸Department of Life Science, Multitasking Macrophage Research Center, Ewha Womans University, Seoul 03760, Korea.
⁹Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
¹⁰CIRNO, Sungkyunkwan University, Suwon 16419, Korea

^*Corresponding author: correspondence to Hye Young Kim

Abstract

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. Additionally, 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 emerging immune cell-based therapeutic target for obesity treatment.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-14)
연구진국내 연구진
분야 생명과학 > 면역학

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