Interferon-γ Safeguards Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis

Chen, Ni; Wang, Chunhui; Zhang, Jingjing; Qu, Luping; Liu, Xiaoman; Lu, Yu; Yang, Wei; Deng, Jingjing; Lorenz, Dorothea; Gao, Pan; Meng, Qinghong; Yan, Xiyun; Blasig, Ingolf E.; Qin, Zhihai

doi:10.1016/j.ajpath.2014.08.019

Cited by 37 publications

(29 citation statements)

References 62 publications

(75 reference statements)

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“…Data were presented as mean ± SEM. L. Flood, et al Journal of Neuroimmunology 337 (2019) 577050 the brain, IFN-γ receptors are broadly expressed in many cell types including microglia, astrocytes, oligodendrocytes, endothelial cells, neural precursor cells and neurons (Hashioka et al, 2010;Hausler et al, 2002;Li et al, 2010;Mizuno et al, 2008;Ni et al, 2014). Notably, the levels of IFN-γ receptor expression differ among cell types, brain regions and species and can alter with external stimuli and in vivo/in vitro conditions (Hashioka et al, 2010;Lee et al, 2006;Li et al, 2010;Robertson et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Flood

Korol

Ekselius

et al. 2019

Journal of Neuroimmunology

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A B S T R A C TThe neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-γ (IFN-γ) is a "pro-inflammatory" cytokine mainly produced by T lymphocytes, activates its corresponding receptor and plays important roles under both homeostatic and inflammatory conditions. However, the impact of IFN-γ on the γ-aminobutyric acid (GABA)-mediated currents in the hippocampus, a major brain region involved in the cognitive function, has not been investigated. Here we detected abundant expression of both IFN-γ receptor subunit gene transcripts (Ifngr1 and Ifngr2) in the rat hippocampus by quantitative PCR. In addition, we pre-incubated rat hippocampal slices with IFN-γ (100 ng/ml) and recorded GABA-activated spontaneous and miniature postsynaptic inhibitory currents (sIPSCs and mIPSCs) and tonic currents in hippocampal CA1 pyramidal neurons by the whole-cell patch-clamp method. The pre-incubation with IFN-γ increased the frequency but not the mean amplitude, rise time or decay time of both sIPSCs and mIPSCs in hippocampal CA1 pyramidal neurons, suggesting a presynaptic effect of IFN-γ. Moreover, the GABAactivated tonic currents were enhanced by IFN-γ. In conclusion, the potentiation of GABAergic currents in hippocampal neurons by IFN-γ may contribute to the disturbed neuronal excitability and cognitive dysfunction during neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Flood

Korol

Ekselius

et al. 2019

Journal of Neuroimmunology

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“…In each field, the mean fluorescence intensity of both CD31 + and Hoechst 33342 + areas was calculated by using Image-Pro plus software (version 6.0). C57BL/6 were originally from Jackson Laboratories and maintained by Zhihai Qin at the Institute of Biophysics, Chinese Academy of Sciences (Beijing, China) (43). Female mice (6-8 weeks old) were used in all the studies.…”

Section: Methodsmentioning

confidence: 99%

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

Zheng¹,

Fang²,

Liu³

et al. 2018

Journal of Clinical Investigation

171

156

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Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

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“…Histopathological analysis was carried out and scored in a blinded fashion as follows. The severity of inflammation was scored according to previously published modified criteria on HE stains [56]. For the demyelination evaluation, we used a semi-quantitative scoring system as described previously [57].…”

Section: Methodsmentioning

confidence: 99%

Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis

et al. 2017

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BackgroundDisruption of blood–brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model.ResultsIn this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production.ConclusionsImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-017-0158-2) contains supplementary material, which is available to authorized users.

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Interferon-γ Safeguards Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis

Cited by 37 publications

References 62 publications

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis

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