Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:204 |
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| Enthalten in: |
American journal of respiratory and critical care medicine - 204(2021), 9 vom: 01. Nov., Seite 1060-1074 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Akimova, Tatiana [VerfasserIn] |
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| Links: |
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| Themen: |
IL-18 |
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| Anmerkungen: |
Date Completed 18.11.2021 Date Revised 26.10.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1164/rccm.202012-4306OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328912913 |
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| 100 | 1 | |a Akimova, Tatiana |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 18.11.2021 | ||
| 500 | |a Date Revised 26.10.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a IL-18 | |
| 650 | 4 | |a lung transplant | |
| 650 | 4 | |a obesity | |
| 650 | 4 | |a primary graft dysfunction | |
| 650 | 4 | |a regulatory T cells | |
| 650 | 7 | |a Interleukin-18 |2 NLM | |
| 700 | 1 | |a Zhang, Tianyi |e verfasserin |4 aut | |
| 700 | 1 | |a Christensen, Lanette M |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhonglin |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Rongxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Negorev, Dmitry |e verfasserin |4 aut | |
| 700 | 1 | |a Samanta, Arabinda |e verfasserin |4 aut | |
| 700 | 1 | |a Sasson, Isaac E |e verfasserin |4 aut | |
| 700 | 1 | |a Gaddapara, Trivikram |e verfasserin |4 aut | |
| 700 | 1 | |a Jiao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Liqing |e verfasserin |4 aut | |
| 700 | 1 | |a Bhatti, Tricia R |e verfasserin |4 aut | |
| 700 | 1 | |a Levine, Matthew H |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Joshua M |e verfasserin |4 aut | |
| 700 | 1 | |a Beier, Ulf H |e verfasserin |4 aut | |
| 700 | 1 | |a Simmons, Rebecca A |e verfasserin |4 aut | |
| 700 | 1 | |a Cantu, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Wilkes, David S |e verfasserin |4 aut | |
| 700 | 1 | |a Lederer, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Michaela |e verfasserin |4 aut | |
| 700 | 1 | |a Christie, Jason D |e verfasserin |4 aut | |
| 700 | 1 | |a Hancock, Wayne W |e verfasserin |4 aut | |
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