Extracellular Vesicle-Associated TWEAK Contributes to Vascular Inflammation and Remodeling During Acute Cellular Rejection

• Published in: JACC. Basic to translational science Vol. 8; no. 5; pp. 439 - 456
• Main Authors: Celik, Selvi, Sadrian, Julia, Grossi, Mario, Czuba, Tomasz, Lundgren, Jakob, Rådegran, Göran, Laurell, Thomas, Smith, J. Gustav, Gidlöf, Olof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2023; Elsevier
• Subjects: acute cellular rejection; chronic rejection; Clinical Medicine; extracellular vesicle; Kirurgi; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Original Research - Clinical; Surgery; TWEAK; PBS; OR; TWEAK; AMR; qRT-PCR; ROC; ISS; MIF; acute cellular rejection; chronic rejection; ACR; IFN; EV; MMP; NF-κB; HCAEC; R; CAV; NTA; EMB; sTWEAK; extracellular vesicle
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2022.09.014

[Display omitted]
•During ACR, vesicular, but not soluble TWEAK, was increased in the circulation in patients who received transplants.•The TWEAK receptor FN14 was expressed in vascular cells of endomyocardial biopsy samples obtained during ACR.•Vesicular TWEAK/FN14 signaling induced proinflammatory gene expression and release of the chemoattractant cytokine MIF from human cardiac endothelial cells.
Acute cellular rejection (ACR) is a leading cause of graft loss and death after heart transplantation despite effective immunosuppressive therapies. The identification of factors that impair graft vascular barrier function or promote immune cell recruitment during ACR could provide new therapeutic opportunities for the treatment of patients who receive transplants. In 2 ACR cohorts, we found the extracellular vesicle-associated cytokine TWEAK to be elevated during ACR. Vesicular TWEAK promoted expression of proinflammatory genes and the release of chemoattractant cytokines from human cardiac endothelial cells. We conclude that vesicular TWEAK is a novel target with potential therapeutic implications in ACR.