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Modulating the PD-1-FABP5 axis in ILC2s to regulate adipose tissue metabolism in obesity
Jongho Ham1, Jaemoon Koh2, Jungeun Kim3
1Laboratory 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.
Obesity impairs immune cells called Type 2 innate lymphoid cells (ILC2s) via osteopontin (OPN) and PD-1 signaling. Blocking this pathway improves metabolic health and offers a new obesity treatment target.
Area of Science:
- Immunology
- Metabolic Disease
- Obesity Research
Background:
- Obesity is linked to metabolic dysregulation and chronic inflammation impacting immune cells in adipose tissue.
- Type 2 innate lymphoid cells (ILC2s) are key regulators of energy homeostasis and potential targets for obesity management.
- Mechanisms of ILC2 dysfunction in obesity and their therapeutic potential require further elucidation.
Purpose of the Study:
- To investigate the role of PD-1 expression on ILC2s in obese adipose tissue.
- To identify molecular pathways regulating ILC2 function in obesity.
- To explore the therapeutic potential of targeting the OPN-PD-1 axis for obesity and related metabolic dysfunctions.
Main Methods:
- Analysis of PD-1 expression on ILC2s in obese adipose tissue.
- Investigation of osteopontin (OPN) and PD-L1 roles in ILC2 dysfunction.
- Pharmacological blockade of PD-1 signaling in obese models.
- Adoptive transfer of PD-1-deficient ILC2s.
- Assessment of metabolic parameters and ILC2 function.
Main Results:
- Obese adipose tissue ILC2s show increased PD-1 expression, leading to exhaustion, reduced cytokine production, and proliferation.
- Elevated OPN levels correlate with higher PD-1 on ILC2s; adipocyte PD-L1 further impairs ILC2 function.
- PD-1 blockade prevents weight gain and metabolic dysfunction; PD-1-deficient ILC2 transfer ameliorates diabetic phenotypes.
- PD-1 signaling downregulates FABP5, impacting ILC2 fatty acid metabolism and energy homeostasis.
Conclusions:
- The OPN-PD-1-FABP5 pathway is a critical regulator of ILC2 function in adipose tissue.
- Targeting this immune cell-based pathway offers a novel therapeutic strategy for obesity and metabolic diseases.
- Findings in mouse models are corroborated by human adipose tissue data, suggesting a conserved mechanism.
