Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

Abstract

Biological mediators secreted during peripheral chronic inflammation reach the bloodstream and may damage the blood–brain barrier (BBB), triggering central nervous system (CNS) disorders. Full-fledged human BBB models are efficient tools to investigate pharmacological pathways and mechanisms of injury at the BBB. We here employed a human in vitro BBB model to investigate the effects of either plasma from inflammatory bowel disease (IBD) patients or tumor necrosis factor α (TNFα), a cytokine commonly released in periphery during IBD, and the anti-inflammatory role of pioglitazone, a peroxisome proliferator-activated receptor γ agonist (PPARγ). The BBB model was treated with either 10% plasma from healthy and IBD donors or 5 ng/mL TNFα, following treatment with 10 µM pioglitazone. Patient plasma did not alter BBB parameters, but TNFα levels in plasma from all donors were associated with varying expression of claudin-5, claudin-3 and ICAM-1. TNFα treatment increased BBB permeability, claudin-5 disarrangement, VCAM-1 and ICAM-1 expression, MCP1 secretion and monocyte transmigration. These effects were attenuated by pioglitazone. Plasma from IBD patients, which evoked higher BBB permeability, also increased ICAM-1 expression, this effect being reversed by pioglitazone. Our findings evidence how pioglitazone controls periphery-elicited BBB inflammation and supports its repurposing for prevention/treating of such inflammatory conditions.

A novel co-culture model for investigation of the effects of LPS-induced macrophage-derived cytokines on brain endothelial cells

“…The RNA-seq analysis revealed increases in IFITM3 expression in bEnd.3 cells co-cultured with LPS-activated Raw264.7 cells but such increases were not found at protein levels by western blot analysis ( Fig 4E and 4F ). Cytokines/chemokines and other secreted molecules during systemic inflammation may impair the BBB integrity [ 55 ]. At the BBB, the most abundant tight junction protein is claudin-5 that is involved in progression of neurodegenerative disorders including AD [ 56 ].…”

“…Catorce and Gevorkian [ 63 ] reviewed LPS-induced murine neuroinflammation models and suggested that peripherally induced inflammation by LPS may trigger neuroinflammation leading to Aβ and/or tau pathology, neurodegeneration and cognitive impairment. Considering increased BBB permeability by LPS [ 55 , 65 ] and fibrinogen infiltration via a leaky BBB [ 85 ], we investigated the BBB permeability by immunofluorescence microscopy using antibodies specific to fibrinogen and CD31, a marker for endothelial cells. We found that fibrinogen fluorescence signals were increased and exclusively limited to the areas positive for CD31 fluorescence signals in LPS-treated mice ( Fig 6 ), indicating that LPS treatment did not induce infiltration of fibrinogen into the brain parenchyma.…”

Factors associated with treatment responses to pioglitazone in patients with steatotic liver disease: A 3‐year prospective cohort study

“…Pioglitazone attenuates inflammation, 29 while both T2DM 30 and fatty liver disease 31 are associated with increased levels of inflammatory markers. Hence, the beneficial effects of pioglitazone on both diabetes and SLD may be the result of an attenuation of inflammation.…”

TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1

“…When ready, HBP were rinsed once with warm DMEM/HG/0.1% BSA and then incubated in DMEM/HG/0.1% BSA supplemented or not with 5 or 10 ng/mL of TNFα. These concentrations were selected based on previous in vitro studies published by us and others [ 64 , 65 , 66 , 67 ].…”