Tatiana Akimova1,2, Tianyi Zhang1,2, Lanette M Christensen1,2, Zhonglin Wang3, Rongxiang Han1,2, Dmitry Negorev1,2, Arabinda Samanta1,2, Isaac E Sasson4,5, Trivikram Gaddapara6, Jing Jiao7, Liqing Wang1,2, Tricia R Bhatti1,2, Matthew H Levine3, Joshua M Diamond8, Ulf H Beier7, Rebecca A Simmons6, Edward Cantu9, David S Wilkes10,11, David J Lederer12, Michaela Anderson12, Jason D Christie9,8, Wayne W Hancock1,2. 1. Division of Transplant Immunology, Department of Pathology and Laboratory Medicine. 2. Biesecker Center for Pediatric Liver Diseases, and. 3. Division of Transplant Surgery and. 4. Department of Obstetrics and Gynecology, and. 5. Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 6. Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 7. Division of Nephrology. 8. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 9. Division of Cardiovascular Surgery, Department of Surgery. 10. Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, School of Medicine, and. 11. Health Lung Transplant Program, Indiana University, Indianapolis, Indiana; and. 12. Division of Pulmonary, Allergy, and Critical Care Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
Abstract
Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.
Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.
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