CXCR3 blockade inhibits T‐cell migration into the CNS during EAE and prevents development of adoptively transferred, but not actively induced, disease

Sporici, Romeo A.; Issekutz, Thomas B.

doi:10.1002/eji.200939975

Cited by 72 publications

(69 citation statements)

References 27 publications

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“…In EAE, both claudin-5 and occludin are downregulated, and claudin-5 has been shown to be the key determinant for BBB breakdown (39). Reductions in TJ protein levels at the impaired BBB and the influx of encephalitogenic T cells generate plaques in the brain parenchyma, resulting in the exacerbation of EAE (40). However, enhanced BBB permeability has been shown to be beneficial for RABV infection, since a permeable BBB allows immune effectors to enter the CNS and clear RABV from the CNS (7,10).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Chai

Wen

Zhou

et al. 2014

J Virol

143

135

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Infection with laboratory-attenuated rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and zonula occludens-1) were decreased in mice infected with laboratoryattenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that gamma interferon (IFN-␥) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-␥ reduced both the disruption of BBB permeability in vivo and the downregulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are due not to RABV infection per se but to virus-induced inflammatory chemokines/cytokines. IMPORTANCEPrevious studies have shown that infection with only laboratory-attenuated, not wild-type, rabies virus (RABV) enhances bloodbrain barrier (BBB) permeability, allowing immune effectors to enter the central nervous system (CNS) and clear RABV from the CNS. This study investigated the mechanism by which RABV infection enhances BBB permeability. It was found that RABV infection enhances BBB permeability by downregulation of tight junction (TJ) protein expression in the brain microvasculature. It was further found that it is not RABV infection per se but the chemokines/cytokines induced by RABV infection that downregulate the expression of TJ proteins and enhance BBB permeability. Blocking some of these cytokines, such as IFN-␥, ameliorated both the disruption of BBB permeability and the downregulation of TJ protein expression. These studies may provide a foundation for developing therapeutics for clinical rabies, such as medication that could be used to enhance BBB permeability.

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Section: Discussionmentioning

confidence: 99%

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Chai

Wen

Zhou

et al. 2014

J Virol

143

135

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“…Treatment of differentiating Th1 cells with I-BET-762 led to down-regulated expression of the chemoattractant IP10; the leuoktriene receptors Cyslt1 and Ltb4r1; RBPj, the main transcriptional mediator of Notch signaling; and the Notch ligand Jagged. These genes are known to regulate T-cell function and the pathogenesis of numerous inflammatory models including EAE (11,14,(22)(23)(24)(25)(26). Additionally, I-BET-762 treatment also led to increased expression of genes characteristic of anergic T cells-Egr-2, IL-10, and the inhibitory cell-surface receptors Lag3, PD-1, and Tim3 (Havcr2), which are downstream targets of NFAT/Egr signaling (27,28).…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of CD4 ⁺ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

Bandukwala

Gagnon

Togher

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

174

180

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Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4 + T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinflammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinflammatory functions of Th1 cells.A promising approach for limiting production of proinflammatory molecules by T cells for treatment of autoimmune disorders has been to target enzymes that facilitate the addition or removal of epigenetic modifications. An additional level of gene regulation derives from proteins that "read" histone and DNA modifications, such as bromodomain-containing proteins that bind acetylated histones. Specifically, BRD2, BRD3, and BRD4-members of the bromodomain and extra-terminal domain (BET) family-contain two tandem N-terminal bromodomains and an extraterminal domain that has been demonstrated to bind a number of chromatin-modifying proteins. The BET family member, BRD4 has a unique C-terminal domain that binds to the positive transcription elongation factor b (P-TEFb; composed of the cyclin-dependent kinase CDK9 and its partner, cyclin T1) complex. BRD4 recruits P-TEFb to acetylated histones, promoting phosphorylation of paused RNA polymerase II (Pol II) and the repressive complexes DSIF and NELF by CDK9, thereby allowing productive mRNA elongation (reviewed in refs. 1 and 2).Given the pivotal role of BET proteins in transcriptional regulation, small molecule compounds that inhibit binding of acetylated histones to bromodomains of BET proteins ...

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“…Furthermore we show no CCR6 + CD8 + T cells, although all of them had infiltrated, and in this and another study we have shown that all of the CD8 + and significant proportions of CD4 + (of any cytokine subset) express CXCR3. We did not pursue the role of CXCR3 + T cells further, and studies of the role of CXCR3 + T cells in EAE continue to yield quite divergent findings (Liu et al, 2005; Muller et al, 2010; Sporici and Issekutz, 2010; Lalor and Segal, 2013). Our data does not exclude that CCR6-negative T cells had once expressed CCR6.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor expression by inflammatory T cells in EAE

Mony¹,

Khorooshi²,

Owens³

2014

Front. Cell. Neurosci.

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Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4+ T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4+ T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 1% of CD4+ T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8+ T cells. CD8+ T cells expressed CXCR3, which was also expressed by CD4+ T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6+ and CXCR3+ CD4+ T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8+ T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4+ T cells expressed CCR6 within infiltrates. CD4-negative CCR6+ cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4+ and CD8+ T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE.

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CXCR3 blockade inhibits T‐cell migration into the CNS during EAE and prevents development of adoptively transferred, but not actively induced, disease

Cited by 72 publications

References 27 publications

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Selective inhibition of CD4 ⁺ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

Chemokine receptor expression by inflammatory T cells in EAE

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CXCR3 blockade inhibits T‐cell migration into the CNS during EAE and prevents development of adoptively transferred, but not actively induced, disease

Cited by 72 publications

References 27 publications

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

Selective inhibition of CD4 + T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

Chemokine receptor expression by inflammatory T cells in EAE

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Selective inhibition of CD4 ⁺ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors