Rapid Remodeling of Tight Junctions during Paracellular Diapedesis in a Human Model of the Blood–Brain Barrier

Abstract

Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that at the tight junctions of the blood-brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed ten-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment (LBRC) is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte-endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.

Viral interactions with the blood-brain barrier: old dog, new tricks

“…Winger and colleagues have observed that human monocytes were able to cross the endothelial tight junction by transiently breaking the local claudin-5 architecture. 72 Non-junctional claudin-5 molcules were rapidly mobilized to form foci surrounding the tight junction gap, which ensured the re-sealing of tight junction after leukocyte extravasation.…”

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

“…TJ disruption precedes overt lesion formation and correlates with clinical severity of EAE (Alvarez et al, 2015; Fabis et al, 2008). Moreover, endothelial TJ degradation promotes paracellular leukocyte migration (Reijerkerk et al, 2008; Winger et al, 2014), whereas overexpression of Claudin1 is protective for EAE (Pfeiffer et al, 2011). Endothelial TJs also prevent serum proteins such as fibrinogen from crossing the BBB, thereby conferring disease protection (Ryu et al, 2015).…”

Современные Возможности Идентификации Новых Молекул-Мишеней Для Фармакологической Коррекции Проницаемости Гематоэнцефалического Барьера

“…Âìåñòå ñ òåì èìåííî â ó÷àñòêàõ âîñïàëåíèÿ èíè-öèèðóþòñÿ ïðîöåññû ðåïàðàòèâíîãî íåéðîãåíåçà è àí-ãèîãåíåçà.  öåëîì, ñòðóêòóðíàÿ öåëîñòíîñòü ÃÝÁ íà-ðóøàåòñÿ èç-çà ñíèaeåíèÿ ýêñïðåññèè èëè íàðóøåíèÿ ñáîðêè áåëêîâ òåñíûõ êîíòàêòîâ, ïîâðåaeäåíèÿ áàçàëü-íîé ìåìáðàíû ÃÝÁ, ãèáåëè ýíäîòåëèîöèòîâ, ÷åìó äî-ïîëíèòåëüíî ñïîñîáñòâóþò èçìåíåíèÿ âçàèìîäåéñò-âèé ìåaeäó êëåòêàìè ýíäîòåëèÿ è ïðèëåaeàùèìè àñòðî-öèòàìè [23,60,78]. Êàê ñëåäñòâèå, â ïåðèôåðè÷åñêîé êðîâè îïðåäåëÿþòñÿ "çàáàðüåðíûå" áåëêè, áåëêè-ìàð-êåðû ïîâðåaeäåíèÿ ÃÝÁ (ôàêòîð ðîñòà ýíäîòåëèÿ ñîñó-äîâ (VEGF), íåéðîòðîôè÷åñêèé ôàêòîð ìîçãà, ãëèàëü-íûé ôèáðèëëÿðíûé êèñëûé áåëîê, íåéðîíñïåöèôè÷å-ñêàÿ åíîëàçà, ìîëåêóëà ãëàâíîãî êîìïëåêñà ãèñòîñîâ-ìåñòèìîñòè II êëàññà, ìîëåêóëà êëåòî÷íîé àäãåçèè àêòèâèðîâàííûõ ëåéêîöèòîâ, ñåìåéñòâî ïðîòåèíîâ S100, êëàóäèíû, îêêëþäèíû, êàäãåðèíû, ñåêðåòèðóå-ìûå àñòðîöèòàìè áåëêè Shh, Wnts, Norrin), à òàêaeå ìå-òàáîëèòû (íàïðèìåð, ãëóòàìàò) è öèòîêèíû, ñâèäå-òåëüñòâóþùèå î ôåíîìåíå "ïðîðûâà" ÃÝÁ) [3,12,40,69].…”