{"doi":"10.1164/rccm.202012-4306oc","title":"Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia–Reperfusion Injury","abstract":"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.","journal":"American Journal of Respiratory and Critical Care Medicine","year":2021,"id":159471,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670519,"name":"Tianyi Zhang","orcid":"0000-0002-6279-5350","position":1,"is_corresponding":false},{"id":482048,"name":"Lanette M. Christensen","orcid":null,"position":2,"is_corresponding":false},{"id":65744,"name":"Zhong Lin Wang","orcid":"0000-0002-5530-0380","position":3,"is_corresponding":false},{"id":299485,"name":"Rongxiang Han","orcid":"0009-0008-5597-3199","position":4,"is_corresponding":false},{"id":671481,"name":"Dmitry Negorev","orcid":null,"position":5,"is_corresponding":false},{"id":481163,"name":"Arabinda Samanta","orcid":"0009-0007-6252-5282","position":6,"is_corresponding":false},{"id":670520,"name":"Isaac Sasson","orcid":"0000-0001-7033-9497","position":7,"is_corresponding":false},{"id":671482,"name":"T. Gaddapara","orcid":null,"position":8,"is_corresponding":false},{"id":231748,"name":"Jing Jiao","orcid":"0000-0002-0018-1353","position":9,"is_corresponding":false},{"id":231751,"name":"Liqing Wang","orcid":"0000-0001-7600-6992","position":10,"is_corresponding":false},{"id":411876,"name":"Tricia Bhatti","orcid":"0000-0001-6511-3514","position":11,"is_corresponding":false},{"id":231763,"name":"Matthew H. Levine","orcid":"0000-0003-4525-5827","position":12,"is_corresponding":false},{"id":322830,"name":"Joshua M. Diamond","orcid":"0000-0002-3695-4637","position":13,"is_corresponding":false},{"id":231766,"name":"Ulf H. Beier","orcid":"0000-0002-3672-572X","position":14,"is_corresponding":false},{"id":400363,"name":"Rebecca A. Simmons","orcid":"0000-0002-2901-8904","position":15,"is_corresponding":false},{"id":260644,"name":"Edward Cantu","orcid":"0000-0003-1105-0129","position":16,"is_corresponding":false},{"id":670521,"name":"David S. Wilkes","orcid":"0000-0001-9758-4169","position":17,"is_corresponding":false},{"id":314630,"name":"David J. Lederer","orcid":"0000-0001-5258-0228","position":18,"is_corresponding":false},{"id":426493,"name":"Michaela R. Anderson","orcid":"0000-0001-9274-7643","position":19,"is_corresponding":false},{"id":337927,"name":"Jason D. Christie","orcid":"0000-0003-0519-218X","position":20,"is_corresponding":false},{"id":231761,"name":"Wayne W. Hancock","orcid":"0000-0002-7211-5291","position":21,"is_corresponding":false},{"id":231752,"name":"Tatiana Akimova","orcid":"0000-0003-2767-8762","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:44:39.550981Z","pmid":"34346860","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}