| First Author | Welser JV | Year | 2017 |
| Journal | J Neuroinflammation | Volume | 14 |
| Issue | 1 | Pages | 217 |
| PubMed ID | 29121970 | Mgi Jnum | J:277498 |
| Mgi Id | MGI:6296359 | Doi | 10.1186/s12974-017-0987-2 |
| Citation | Welser JV, et al. (2017) Endothelial alpha6beta4 integrin protects during experimental autoimmune encephalomyelitis-induced neuroinflammation by maintaining vascular integrity and tight junction protein expression. J Neuroinflammation 14(1):217 |
| abstractText | BACKGROUND: Extracellular matrix (ECM) proteins play critical functions regulating vascular formation and function. Laminin is a major component of the vascular basal lamina, and transgenic mice deficient in astrocyte or pericyte laminin show defective blood-brain barrier (BBB) integrity, indicating an important instructive role for laminin in cerebral blood vessels. As previous work shows that in the normal brain, vascular expression of the laminin receptor alpha6beta4 integrin is predominantly restricted to arterioles, but induced on all vessels during neuroinflammation, it is important to define the role of this integrin in the maintenance of BBB integrity. METHODS: alpha6beta4 integrin expression was analyzed using dual immunofluorescence (dual-IF) of brain sections taken from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To investigate the role of endothelial alpha6beta4 integrin, transgenic mice lacking beta4 integrin in endothelial cells (beta4-EC-KO) and wild-type (WT) littermates were subject to EAE, and clinical score and various neuropathological parameters were examined by immunofluorescence. In addition, beta4 integrin null brain endothelial cells (BECs) were examined in culture for expression of tight junction proteins using immunocytochemistry and flow cytometry. RESULTS: Cerebrovascular expression of beta4 integrin was markedly upregulated during EAE progression, such that by the acute stage of EAE (day 21), the vast majority of blood vessels expressed beta4 integrin. In the EAE model, while the beta4-EC-KO mice showed the same time of disease onset as the WT littermates, they developed significantly worse clinical disease over time, resulting in increased clinical score at the peak of disease and maintained elevated thereafter. Consistent with this, the beta4-EC-KO mice showed enhanced levels of leukocyte infiltration and BBB breakdown and also displayed increased loss of the endothelial tight junction proteins claudin-5 and ZO-1. Under pro-inflammatory conditions, primary cultures of beta4KO BECs also showed increased loss of claudin-5 and ZO-1 expression. CONCLUSIONS: Taken together, our data suggest that alpha6beta4 integrin upregulation is an inducible protective mechanism that stabilizes the BBB during neuroinflammatory conditions. |
