Activated Microglia Disrupt the Blood-Brain Barrier and Induce Chemokines and Cytokines in a Rat in vitro Model

Abstract

Severe neuroinflammation is associated with blood brain barrier (BBB) disruption in CNS diseases. Although microglial activation and the subsequent changes in cytokine/chemokine (C/C) concentrations are thought to be key steps in the development of neuroinflammation, little data are available concerning the interaction of microglia with BBB cells. In this study, we investigated this interaction by adding LPS-activated microglia (LPS-MG) to the abluminal side of a BBB model composed of endothelial cells (EC), pericytes (Peri) and astrocytes (Ast). We then examined the abluminal concentrations of 27 C/Cs and the interactions between the LPS-MG and BBB cells. LPS-MG caused collapse of the BBB, revealed by decreases in the trans-endothelial electrical resistance (TEER) and by changes in the expression levels of tight junction (TJ) proteins. Under these conditions, 19 C/Cs were markedly increased on the abluminal side. Unexpectedly, although LPS-MG alone released 10 of the 19 C/Cs, their concentrations were much lower than those detected on the abluminal side of the BBB model supplemented with LPS-MG. Co-culture of LPS-MG with Ast caused marked increases in 12 of the 19 C/Cs, while co-culture of LPS-MG with EC and Peri resulted in a significant increase in only 1 of the 19 C/Cs (fractalkine). These results suggest that C/C dynamics in this system are not only caused by activated microglia but also are due to the interaction between activated microglia and astrocytes.

Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports

“…1 ). For example, animal studies showed that MAP could disintegrate endothelial tight junction proteins via several mechanisms [ 43 , 45 ] including releasing pro-inflammatory cytokines and chemokines, upregulating inducible pro-inflammatory molecules such as matrix metalloproteinase (MMPs) among others, and promoting oxidative stress (Fig. 1 ) [ 40 , 41 , 45 ].…”

“…For example, animal studies showed that MAP could disintegrate endothelial tight junction proteins via several mechanisms [ 43 , 45 ] including releasing pro-inflammatory cytokines and chemokines, upregulating inducible pro-inflammatory molecules such as matrix metalloproteinase (MMPs) among others, and promoting oxidative stress (Fig. 1 ) [ 40 , 41 , 45 ]. BBB breakdown, in turn, can potentially facilitate deleterious crosstalk between brain innate and peripheral adaptive immunity, thereby creating a self-perpetuating neuroinflammatory milieu [ 40 , 41 , 43 ].…”

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

“…In response to TNFα, rat brain pericytes in vitro produce IL6 and macrophage inflammatory protein 1 (MIP1), which trigger microglial activation (Matsumoto et al, 2014). Activated microglia disrupt the BBB, which triggers angiogenesis (Dudvarski Stankovic et al, 2016;Shigemoto-Mogami et al, 2018). In the mouse brain, pericytes initially respond to the systemic inflammation within 2 h and secrete CCL2 before the response of astrocytes or microglia (Duan et al, 2018).…”

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…Disruption of the BBB in several mouse models of neuropsychiatric or inflammatory diseases has been shown to affect microglial function, while dynamic neuroimmune interactions were described at the BBB in both health and diseased sates (Merlini et al, 2012;Borjini et al, 2019;Haruwaka et al, 2019). Although causal evidence is needed, multiple studies have found that microglial reactivity worsens BBB integrity in pathological states and that administration of the anti-inflammatory drug minocycline can improve BBB function (Yenari et al, 2006;da Fonseca et al, 2014;Shigemoto-Mogami et al, 2018). More work is still needed to understand whether or how the interplay between BBB dysfunction and microglia abnormalities contribute to the pathogenesis of SCZ.…”