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

Journal Article · Tue Aug 09 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0160875· OSTI ID:1377835

Huang, Li -Yun ^[1]; Stuart, Christine ^[1]; Takeda, Kazuyo ^[2]; D’Agnillo, Felice ^[2]; Golding, Basil ^[1]; Deli, Mária A. ^[3]

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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)

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.

• Research Organization: Food and Drug Administration, Silver Spring, Maryland (United States)
• Sponsoring Organization: USDOE
• OSTI ID: 1377835
• Journal Information: PLoS ONE, Vol. 11, Issue 8; ISSN 1932-6203
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

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