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Oncostatin M Induces Barrier Dysfunction in Human Brain Microvascular Endothelium via Snail‐Dependent Repression of TAMPs
Author(s) -
Wertz Travis S,
Hoettels Brian A,
Tawara Ken,
Oxford Julia T,
Jorcyk Cheryl L,
Beard Richard S
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.679.9
Subject(s) - oncostatin m , adherens junction , occludin , microbiology and biotechnology , endothelial stem cell , endothelium , tight junction , blood–brain barrier , neuroinflammation , endothelial dysfunction , cytokine , chemistry , biology , cell , immunology , inflammation , cadherin , neuroscience , interleukin 6 , endocrinology , biochemistry , in vitro , central nervous system
Homeostasis of barrier integrity in brain microvessels is maintained by dynamic regulation of endothelial cell‐cell adhesive proteins. During aberrant inflammatory responses, a host of factors act upon the endothelium to modify these proteins and diminish barrier integrity, leading to leakage of plasma components, neurotoxic substances, and potentially edema. The pleiotropic cytokine oncostatin M (OSM) is one such factor, which has been shown to be elevated in several inflammatory conditions, such as multiple sclerosis, that are associated with increased microvascular leakage. Indeed, recent evidence suggests that OSM may directly induce brain endothelial cell barrier dysfunction, but the mechanisms remain unclear. The objective of this study was to determine the effect of OSM on the barrier integrity of human brain microvascular endothelial cells (BMVECs). First, we confirmed that BMVECs were responsive to OSM by measuring activation of STAT3, which is known to be downstream of OSM receptor signaling in other cell types. Indeed, OSM triggered phosphorylation of STAT3 at Y705 in BMVECs as early as 15 minutes following stimulation. Next, we identified that treating BMVEC monolayers with OSM promoted barrier dysfunction, as demonstrated by time‐and‐dosage‐dependent decreases of transendothelial electrical resistance (TER). Concomitant with TER changes, OSM induced a significant decrease in the tight‐junction‐associated MARVEL proteins (TAMPs) occludin and tricellulin. Interestingly, OSMs effect on downregulation of endothelial cell‐cell junctional proteins appears to be exclusive to TAMPs, as there were no noticeable changes in claudin‐ 1, 3, 5, 12 or the adherens junction protein VE‐cadherin. Since it has previously been identified in epithelial cells that occludin can be negatively regulated by the transcription factor SNAI1, or Snail, we evaluated a potential role of Snail in OSM‐mediated barrier dysfunction of BMVECs. At baseline, there was minimal detection of Snail; however, OSM induced a robust upregulation of Snail protein preceding the onset of barrier dysfunction. Finally, siRNA‐mediated knockdown of SNAI1 both increased baseline levels of TAMPs and attenuated OSM‐induced TAMP downregulation and BMVEC barrier dysfunction. In conclusion, elevated OSM induces human brain endothelial barrier dysfunction in a Snail‐dependent manner, and further exploration of this signaling pathway in brain endothelium holds multiple facets of therapeutic potential. Support or Funding Information Supported by The Birt Family and NIH grants: P20 GM109095 and 2P20GM103408.