Saiprasad Gowrikumar, Aria Tarudji, Brandon Z McDonald, Sai Sindhura Balusa, Forrest M Kievit, Punita Dhawan
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引用次数: 0
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in patients. Brain microvasculature endothelial cells form the blood-brain barrier (BBB) which functions to maintain a protective barrier for the brain from the passive entry of systemic solutes. As a result of the cellular disruption caused by TBI, the BBB is compromised. Tight junction disruption in the endothelium of the BBB has been implicated in this response, but the underlying mechanisms remain unresolved. We utilized various in vivo models of severe to mild TBI as well as in vitro exposure of brain endothelial cells (bEND.3) to analyze conditions encountered following TBI to gain mechanistic insight into alterations observed at the BBB. We found that claudin-1 (CLDN1), was significantly increased in the brain endothelium both in vivo and in vitro. The observed increase of CLDN1 expression correlated with down-regulation of claudin-5 (CLDN5), occludin (OCLN), and zonula occludens (ZO-1), thereby altering BBB integrity by decreasing TEER and increasing permeability. Knockdown of CLDN1 in these pathogenic conditions showed stability of the endothelial junctional proteins. A decline in the epigenetic regulator silent information regulator family protein 1 (SIRT1), a member of the NAD+ dependent protein deacetylases, coincided with this upregulation of CLDN1. Indeed, the quenching of oxidative stress through NAC treatment was able to reduce injury-induced upregulation of CLDN1 in vitro. Mechanistically, an SRC-dependent tyrosine phosphorylation of OCLN and ZO-1 in CLDN1-modulated conditions was observed. Our findings will provide new insights into BBB deregulation and new possible treatment opportunities for TBI.
期刊介绍:
Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.