Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplantation. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD.
We hypothesized that T-regulatory (Treg) cells are able to dampen early ischemia/reperfusion events and thereby decrease risk of PGD, whereas that action is impaired in obese recipients.
We evaluated Treg, T cells and inflammatory markers, plus clinical data, in 79 lung and 41 liver or kidney transplant recipients and studied two groups of mice on high fat diet (HFD), who developed (“inflammatory” HFD) or not (“healthy” HFD) low-grade inflammation with decreased Treg function.
We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Treg 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 Treg from obese mice fail to control PGD, while IL-18 inhibition ameliorates lung inflammation. The IL-18 driven impairment in Treg suppressive function pre-transplant was associated with increased risk and severity of PGD in clinical lung transplant recipients.
Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Treg suppressive function along with IL-18 levels may serve as screening tools to identify pre-transplant obese recipients with increased risk of PGD.