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Vesicle-Associated Tweak is Increased During Acute Cellular Rejection and Contributes to Endothelial Inflammation

O. Gidlof, J. Sadrian, M. Grossi, S. Alcevska, J. Lundgren, G. Rådegran, G. Smith

Cardiology, Lund University, Lund, Sweden

Meeting: 2020 American Transplant Congress

Abstract number: A-350

Keywords: Endothelial activation, Heart, Rejection

Session Information

Session Name: Poster Session A: Acute Rejection

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

 Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Extracellular vesicles (EVs) are released from immune cells upon activation and play direct roles in allograft tolerance and rejection, in part through delivery of encapsulated or membrane-bound cytokines. Through proteomic profiling of EV proteins isolated from plasma of cardiac allograft recipients we recently identified the cytokine TNF-related weak inducer of apoptosis (TWEAK) to be elevated during acute cellular rejection. TWEAK elicits pro-inflammatory effects on endothelial cells through its receptor FN14, primarily mediated via NF-Kappa B signaling. The purpose of this study was to explore a possible role for vesicular TWEAK in ACR pathobiology.

*Methods: The presence of TWEAK on plasma EVs was assessed with immunogold labeling and transmission electron microscopy (TEM), fluorescent nanoparticle tracking analysis and ELISA. TWEAK+EVs were quantified in plasma of cardiac allograft recipients with ACR and non-ACR controls using immunostaining and flow cytometry. The expression and localization of the TWEAK receptor FN14 was analyzed with immunohistochemistry on endomyocardial biopsies from patients with ACR and non-ACR controls and on human coronary artery endothelial cells (HCAECs) using western blot. HCAECs were nucleofected with a NFKB reporter plasmid and stimulated with TWEAK+EVs and/or recombinant TWEAK.

*Results: We show that TWEAK is present on the surface of ~200-800 nm vesicles and that approximately 25% of circulating TWEAK is associated with EVs. Using flow cytometry, we confirm that the plasma concentration of TWEAK+EVs is significantly elevated (p<0.05) in patients with ACR (n=17) compared to non-ACR controls (n=32). We observe a drastic and widespread upregulation of FN14 expression in cardiac tissue from patients with ACR compared to non-ACR controls. In vitro, TWEAK+ EVs potentiate TWEAK-induced NF-Kappa B signaling in HCAECs (p<0.001).

*Conclusions: We provide evidence for direct involvement of the TWEAK/FN14 axis in ACR, mediated by extracellular vesicles and potentially contributing to exacerbation of graft endothelial inflammation.

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To cite this abstract in AMA style:

Gidlof O, Sadrian J, Grossi M, Alcevska S, Lundgren J, Rådegran G, Smith G. Vesicle-Associated Tweak is Increased During Acute Cellular Rejection and Contributes to Endothelial Inflammation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/vesicle-associated-tweak-is-increased-during-acute-cellular-rejection-and-contributes-to-endothelial-inflammation/. Accessed May 10, 2025.

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