Next Generation In Vitro Models of the Human Blood - Brain/Cerebrospinal Fluid Barrier

Editorial

30 January 2024

Editorial: Next generation in vitro models of the human blood - brain/cerebrospinal fluid barrier

Randy S. Daughters

Lisa Julian

Erin Knock

and

Stephanie M. Willerth

2,758 views

0 citations

Editors

Erin Knock

Stemcell Technologies Inc.

Stephanie Michelle Willerth

University of Victoria

Lisa Marie Julian

Department of Biological Sciences, Faculty of Science, Simon Fraser University

Randy Daughters

Emulate Inc.

Impact

Potential mechanisms of the blood-brain barrier disruption by SARS-CoV-2 and their implication in the increased permeability of drugs into the brain. SARS-CoV-2 interacts with the BBB by binding the viral S protein and the ACE2 receptors of the vascular endothelium. Other proteins, such as NRP1, TMPRSS2, BSG, and Cathepsin L, are also involved. Proteolytic activation of the S protein is a crucial step in SARS-CoV-2 infection and occurs at the S1/S2 site by the action of furin protease. After binding to ACE2, the S protein undergoes further cleavage mediated by TMPRSS2 at the S2’ site to facilitate the fusion of the virus with the host cell membrane. Once the infection of BBB ECs has occurred, viral replication continues, promoting the activation of inflammatory mechanisms, which include the release of proinflammatory cytokines. The release of primary proinflammatory cytokines, such as IFN-γ and TNF-α, leads to the activation of immune cells, ECs, astrocytes, and microglia. Activated microglial cells induce the release of cytokines such as IL-1, IL-6, and TNF-α, which further activate astrocytes. Activated astrocytes release mediators, such as TNF, prostaglandins, glutamate, ROS, and nitric oxide, which are implicated in neurotoxicity induced by neuroinflammation. IL-6 can cause excessive activation of the complement system and coagulation cascades that contribute to a harmful cytokine storm cycle, destabilizing TJs and damaging BBB ECs, increasing vascular permeability. Lysis of infected ECs alters the permeability of the BBB. The virus promotes an increase in the expression of MMP9 (responsible for the degradation of collagen IV, an essential component of the basal membrane), promoting the rupture of the BBB. S protein promotes RhoA activation, which induces cytoskeletal restructuring and TJs disassembly, altering BBB permeability. Following these possible mechanisms, the BBB is exposed to the passage of xenobiotics, including viral particles and drugs. Drugs such as oseltamivir have limited penetration through the BBB because it is a substrate for P-glycoprotein. However, in a clinical setting, BBB disruption could increase oseltamivir penetration into the brain, potentially leading to increased unwanted CNS effects. On the contrary, tocilizumab has a limited ability to cross the BBB; however, its therapeutic effect would be enhanced with a more permeable BBB.

Mini Review

14 March 2023

Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain

Héctor Hernández-Parra

, 7 more and

Gerardo Leyva-Gómez

6,991 views

29 citations

Original Research

25 September 2023

Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions

Arya Lekshmi Nair

, 6 more and

Nienke R. Wevers

8,327 views

10 citations

Remarkable increase in proliferation of microglia and macrophages in the CVOs and neighboring brain regions in adult mouse brain after LPS administration. Intraperitoneal administration of 100 μg/kg LPS induces a robust increase of Iba1+ BrdU+ proliferating microglia and macrophages in the OVLT (arrowheads) and medial preoptic area (MPA; arrows) (A), the SFO (arrowheads) and ventral hippocampal commissure (vhc; arrows) (B), and the AP (arrowheads) and solitary nucleus (Sol; arrows) (C). High magnification reveals many Iba1+ BrdU+ proliferating microglia and macrophages in the CVOs (D–F). Scale bars = 100 (A) and 50 μm (D). Photographs are rearranged with permission from Springer Nature (Furube et al., 2015, 2018). The density of PU.1+ microglia and macrophages is significantly elevated in the CVOs and neighboring brain regions on the 5th and 10th day after administration of 100 μg/kg and 1 mg/kg LPS, but returns to almost normal levels on the 20th day (G). The i.c.v. infusion of the mitotic inhibitor AraC significantly delays body weight recovery after 5 mg/kg administration (H). 10N, dorsal motor nucleus of vagus nerve; 12N, hypoglossal nucleus; AP, area postrema; fi, fimbria; MnPO, median preoptic area; MPA, medial preoptic area; OVLT, organum vasculosum of the lamina terminalis; SFO, subfornical organ; Sol, solitary nucleus; vhc, ventral hippocampal commissure; VMH, ventromedial hypothalamic nucleus. *p < 0.05, **p < 0.01, ***p 0.001 vs. the control by an ANOVA with Tukey’s post-hoc test. Graphs are rearranged with permission from Springer Nature [(A) Furube et al., 2018] and Elsevier B.V. [(B) Torii et al., 2022].

Review

06 October 2022

Glial functions in the blood-brain communication at the circumventricular organs

Seiji Miyata

The circumventricular organs (CVOs) are located around the brain ventricles, lack a blood-brain barrier (BBB) and sense blood-derived molecules. This review discusses recent advances in the importance of CVO functions, especially glial cells transferring periphery inflammation signals to the brain. The CVOs show size-limited vascular permeability, allowing the passage of molecules with molecular weight <10,000. This indicates that the lack of an endothelial cell barrier does not mean the free movement of blood-derived molecules into the CVO parenchyma. Astrocytes and tanycytes constitute a dense barrier at the distal CVO subdivision, preventing the free diffusion of blood-derived molecules into neighboring brain regions. Tanycytes in the CVOs mediate communication between cerebrospinal fluid and brain parenchyma via transcytosis. Microglia and macrophages of the CVOs are essential for transmitting peripheral information to other brain regions via toll-like receptor 2 (TLR2). Inhibition of TLR2 signaling or depletion of microglia and macrophages in the brain eliminates TLR2-dependent inflammatory responses. In contrast to TLR2, astrocytes and tanycytes in the CVOs of the brain are crucial for initiating lipopolysaccharide (LPS)-induced inflammatory responses via TLR4. Depletion of microglia and macrophages augments LPS-induced fever and chronic sickness responses. Microglia and macrophages in the CVOs are continuously activated, even under normal physiological conditions, as they exhibit activated morphology and express the M1/M2 marker proteins. Moreover, the microglial proliferation occurs in various regions, such as the hypothalamus, medulla oblongata, and telencephalon, with a marked increase in the CVOs, due to low-dose LPS administration, and after high-dose LPS administration, proliferation is seen in most brain regions, except for the cerebral cortex and hippocampus. A transient increase in the microglial population is beneficial during LPS-induced inflammation for attenuating sickness response. Transient receptor potential receptor vanilloid 1 expressed in astrocytes and tanycytes of the CVOs is responsible for thermoregulation upon exposure to a warm environment less than 37°C. Alternatively, Na_x expressed in astrocytes and tanycytes of the CVOs is crucial for maintaining body fluid homeostasis. Thus, recent findings indicate that glial cells in the brain CVOs are essential for initiating neuroinflammatory responses and maintaining body fluid and thermal homeostasis.

7,227 views

20 citations