Presenting Author: Maria Serena Longhi
, Associate Professor of Anesthesia at Beth Israel Deaconess Med. Ctr., Harvard Med. Sch.
Abstract:
Treg impairment in inflammatory bowel disease (IBD) derives from dysfunctional CD39, an ectoenzyme that modulates cell metabolism by hydrolyzing ATP/ADP into immunosuppressive adenosine. CD39 is regulated by an endogenous-antisense-RNA (CD39-AS), which is heightened in Tregs of IBD patients. Increased CD39-AS levels in IBD-Tregs are associated with impaired CD39 and directly correlate with Montreal type, a marker of disease severity. Given the close links between CD39 and cell metabolism, we investigated whether CD39-AS impacts Treg suppression and metabolic function in IBD and health. Tregs isolated from the peripheral blood of IBD patients and controls were exposed to FANA-oligos targeting CD39-AS. Silencing of CD39-AS resulted in increased adenosine levels in control and IBD-Tregs; and in enhanced Treg suppression in IBD. Blockade of CD39-AS resulted in downregulation of genes associated with metabolic pathways like glucose transport (SLC2A1, encoding for GLUT1) and glycolysis (HK2), as determined by NanoString analysis. Treatment with CD39-AS FANA-oligos decreased Treg glucose uptake and extracellular acidification rate in both control and IBD-Tregs. Inhibition of GLUT1 using fasentin boosted Treg suppression, even in the presence of high glucose. In conclusion, CD39-AS modulates Treg metabolism by favoring glucose transport and glycolysis. Silencing of CD39-AS might restore Treg function in IBD by impacting these metabolic pathways.
Endogenous CD39 antisense controls Treg metabolism in inflammatory bowel disease
Category
Poster and Podium (Block Symposium)
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Date: May 6 Presentation Time: 02:15 PM to 03:30 PM Room: Exhibit Hall F1