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Title: Poly(I:C) Induces Human Lung Endothelial Barrier Dysfunction by Disrupting Tight Junction Expression of Claudin-5

Viral infections are often accompanied by pulmonary microvascular leakage and vascular endothelial dysfunction via mechanisms that are not completely defined. Here, we investigated the effect of the Toll-like receptor 3 (TLR3) ligand polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA (dsRNA) commonly used to simulate viral infections, on the barrier function and tight junction integrity of primary human lung microvascular endothelial cells. Poly(I:C) stimulated IL-6, IL-8, TNFα, and IFNβ production in conjunction with the activation of NF-κB and IRF3 confirming the Poly(I:C)-responsiveness of these cells. Poly(I:C) increased endothelialmonolayer permeability with a corresponding dose- and time-dependent decrease in the expression of claudin-5, a transmembrane tight junction protein and reduction of CLDN5 mRNA levels. Immunofluorescence experiments revealed disappearance of membrane-associated claudin-5 and co-localization of cytoplasmic claudin-5 with lysosomal-associated membrane protein 1. Chloroquine and Bay11-7082, inhibitors of TLR3 and NF-κB signaling, respectively, protected against the loss of claudin-5. Altogether, these findings provide new insight on how dsRNA-activated signaling pathways may disrupt vascular endothelial function and contribute to vascular leakage pathologies.
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [3]
  1. Food and Drug Administration, Silver Springs, MD (United States)
  2. Food and Drug Administration, Silver Spring, MD (United States)
  3. Hungarian Academy of Sciences (Hungary)
Publication Date:
Accepted Manuscript
Journal Name:
Additional Journal Information:
Journal Volume: 11; Journal Issue: 8; Journal ID: ISSN 1932-6203
Public Library of Science
Research Org:
Food and Drug Administration, Silver Spring, Maryland (United States)
Sponsoring Org:
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; immune receptor signaling; cell membranes; nuclear straining; tight junctions; toll-like receptors; endothelial cells; fluorescence imaging; permeability
OSTI Identifier: