Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.
Am J Respir Crit Care Med
; 204(9): 1060-1074, 2021 11 01.
Article
in En
| MEDLINE
| ID: mdl-34346860
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 MainResults:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Reperfusion Injury
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Lung Transplantation
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T-Lymphocytes, Regulatory
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Interleukin-18
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Acute Lung Injury
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Primary Graft Dysfunction
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Obesity
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Adult
/
Aged
/
Aged80
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Animals
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Am J Respir Crit Care Med
Journal subject:
TERAPIA INTENSIVA
Year:
2021
Type:
Article