IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

Abstract

Transendothelial migration (TEM) of Th1 and Th17 cells across the blood-brain barrier (BBB) has a critical role in the development of experimental autoimmune encephalomyelitis (EAE). How cytokines produced by inflammatory Th1 and Th17 cells damage the endothelial BBB and promote transendothelial migration of immune cells into the central nervous system (CNS) during autoimmunity is not understood. We therefore investigated the effect of various cytokines on brain endothelial cells. Among the various cytokines tested, such as Th1 (IFN-γ, IL-1α, IL-1β, TNF-α, IL-12), Th2 (IL-3, IL-4, IL-6 and IL-13), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23, GM-CSF) and Treg-specific cytokines (IL-10 and TGF-β), IFN-γ predominantly showed increased expression of ICAM-1, VCAM-1, MAdCAM-1, H2-K and I-A molecules on brain endothelial cells. Furthermore, IFN-γ induced transendothelial migration of CD4 T cells from the apical (luminal side) to the basal side (abluminal side) of the endothelial monolayer to chemokine CCL21 in a STAT-1-dependent manner. IFN-γ also favored the transcellular route of TEM of CD4 T cells. Multicolor immunofluorescence and confocal microscopic analysis showed that IFN-γ induced relocalization of ICAM-1, PECAM-1, ZO-1 and VE-cadherin in the endothelial cells, which affected the migration of CD4 T cells. These findings reveal that the IFN-γ produced during inflammation could contribute towards disrupting the BBB and promoting TEM of CD4 T cells. Our findings also indicate that strategies that interfere with the activation of CNS endothelial cells may help in controlling neuroinflammation and autoimmunity.

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

“…Importantly, IFN-γ, which is shown to be elevated in PD patients, promotes migration of CD4+ T-cells across the BBB (Sonar et al, 2017). Furthermore, a study by González et al (2013), in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD showed that D3R expression on CD4+ T-cells may contribute to dopaminergic neuron degeneration in the SN.…”

Blood–brain barrier and its function during inflammation and autoimmunity

“…Additionally, they also show remarkably reduced transcytosis, which restricts vesicle‐driven transcellular entry of solute molecules from the luminal to the abluminal side . The consequence of these paracellular and transcellular barriers impart endothelial polarity with distinct luminal (apical) and abluminal (basal) membranes, which controls the directional movement of ions, molecules, and immune cells from circulation to the CNS and vice versa . BBB ECs have specific transporters mostly abundant in the luminal surface that allows the movement of nutrients across the BBB into the CNS .…”

“…Several inflammatory mediators such as IL‐1β, IL‐6, IL‐17, IFN‐γ, TNF‐α, and CCL2 through various known signaling mechanisms either reduce the expression of TJ proteins such as occludin, claudin‐5, ZO‐1, JAM‐A, or alter the localization of these junctional molecules and therefore disturb the BBB integrity . These cytokines also up‐regulate the expression of chemokines and CAMs on the luminal surface of BBB endothelium . The role of tumor necrosis factor superfamily members and molecules that affect the differentiation and function of inflammatory CD4 + T cells and their TEM in CNS during in neuroinflammation and autoimmunity is well known .…”

“…These cytokines also up‐regulate the expression of chemokines and CAMs on the luminal surface of BBB endothelium . The role of tumor necrosis factor superfamily members and molecules that affect the differentiation and function of inflammatory CD4 + T cells and their TEM in CNS during in neuroinflammation and autoimmunity is well known . Additionally, such proinflammatory mediators are also known to induce the expression of matrix metalloproteinases (MMPs) such as MMP2 and MMP9 in ECs, astrocytes, microglial cells, monocytes and macrophages that help in breaching the basement membrane components and facilitate transmigration of inflammatory cells into the CNS parenchyma .…”

“…It has been increasingly appreciated that almost all the components of the BBB respond to the inflammation, and regulate the diffusion of soluble inflammatory mediators and transmigration of effector immune cells into the CNS parenchyma that dictates the disease activity. Recently, we have shown that Th1 cytokine, IFN‐γ disrupt the endothelial barrier and induces TEM of CD4 + T cells from the apical to the basal side by inducing the redistribution of ICAM‐1 in the STAT‐1 dependent manner . The therapeutic strategies designed to inhibit and/or treat BBB defect may represent a novel treatment option for neuronal inflammation and autoimmunity.…”