Title: Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.
Authors: Akimova, Tatiana; Zhang, Tianyi; Christensen, Lanette M; Wang, Zhonglin; Han, Rongxiang; Negorev, Dmitry; Samanta, Arabinda; Sasson, Isaac E; Gaddapara, Trivikram; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R; Levine, Matthew H; Diamond, Joshua M; Beier, Ulf H; Simmons, Rebecca A; Cantu, Edward; Wilkes, David S; Lederer, David J; Anderson, Michaela; Christie, Jason D; Hancock, Wayne W
Published In Am J Respir Crit Care Med, (2021 11 01)
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.
PubMed ID: 34346860
MeSH Terms: Acute Lung Injury/etiology*; Acute Lung Injury/physiopathology; Adult; Aged; Aged, 80 and over; Animals; Female; Humans; Interleukin-18/metabolism*; Lung Transplantation/adverse effects*; Male; Mice; Mice, Obese; Middle Aged; Obesity/complications*; Primary Graft Dysfunction/etiology*; Primary Graft Dysfunction/physiopathology; Reperfusion Injury/etiology*; Reperfusion Injury/physiopathology; T-Lymphocytes, Regulatory/metabolism*