Molecular alterations of the blood–brain barrier under inflammatory conditions: The role of endothelial to mesenchymal transition

Abstract

Impairment of the protective properties of the blood-brain barrier (BBB) is a key event during numerous neurological diseases, including multiple sclerosis (MS). Under these pathological conditions, the specialized brain endothelial cells (BECs) lose their protective function leading to neuroinflammation and neurodegeneration. To date, underlying mechanisms for this loss of function remain unclear. Endothelial to mesenchymal transition (EndoMT) is a dynamic process by which endothelial cells (ECs) dedifferentiate into mesenchymal cells and as a result lose their specific phenotype and function. As yet, little is known about the involvement of this process in the impaired function of the BECs under pathological conditions such as MS. Interestingly, several signaling pathways that can induce EndoMT are also involved in different central nervous system (CNS) pathologies associated with BBB dysfunction. In this review, we first discuss the structure and function of the BBB highlighting the changes that occur during MS. Next, we will summarize recent findings on the pathways underlying EndoMT, and finally, we will discuss the potential role of EndoMT during BBB dysfunction in neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

Gene expression profile of endothelial cells during perturbation of the gut vascular barrier

“…36 EndoMT is an essential mechanism of development of different organs but it has also been described in different diseases such as cardiac fibrosis, metastatic cancer, retina diabetes and sepsis. [36][37][38] Interestingly, meningeal pathogens, such as group B Streptococcus, are able to induce EndoMT in the BBB activating Snail1 which represses tight junction protein gene expression resulting in an increased bacterial penetration into the brain parenchyma.…”

“…36 EndoMT is an essential mechanism of development of different organs but it has also been described in different diseases such as cardiac fibrosis, metastatic cancer, retina diabetes and sepsis. [36][37][38] Interestingly, meningeal pathogens, such as group B Streptococcus, are able to induce EndoMT in the BBB activating Snail1 which represses tight junction protein gene expression resulting in an increased bacterial penetration into the brain parenchyma. 39 Similarly, we found that Snail2, another important transcription factor driving EndoMT, 36 is up-regulated by Salmonella infection in purified gut endothelial cells together with genes characteristic of mesenchymal cells, such as a-smooth muscle actin (Acta2) and several genes encoding for extracellular matrix proteins characteristic of fibrosis including fibronectin (Fn1), tenascin-C (TnC) and type-I collagen (Col1a1, Col1a2) (Fig.…”

The microbiome, microbial-generated proinflammatory neurotoxins, and Alzheimer's disease

“…It has been known for some time that the functional optimization of the microbiome–GI tract–CNS axis, via studies on GI tract “microbial imbalance” or “dysbiosis” in germ-free animals, the administration of probiotics, and bacterial infections with enteric pathogens have strong effects that can ultimately modulate cognitive behavior, learning, memory, and healthy brain aging. 22,23 Recent studies underscore the concept that just as exercise requires the replenishment of efficient and sufficient energy stores, diets that support optimal CNS and cognitive health require both a healthy dietary intake and sufficient dietary fiber to ensure the “best possible performance” of our microbiome, 14–20 leading to the optimization of microbial speciation and stoichiometry, functional symbiosis, and communication along the microbiome–GI tract–CNS axis.…”

“…16–21 Taken together, these recent findings indicate that fragilysin’s pathogenic actions (1) interrupt the integrity of intercellular adhesion; 15,18,19 (2) increase mucosal permeability and the permeability of the intestinal epithelium to GI tract contents; 14–17 and (3) induce epithelial cell–cell detachment, laying the morphologic basis for a compromised and “leaky” GI tract barrier. 17–23 …”

Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens

“…Disruption of the blood-brain barrier caused by a neurosurgical operation could result in inflammatory reactions in the CNS, which is known as surgical brain injury (SBI)2. The main function of the blood-brain barrier is to provide the optimal microenvironment for proper neuronal function3. After SBI or traumatic brain injury (TBI) destroys the blood-brain barrier, antigens of the brain tissue are released into systemic circulation.…”