Astrocytes are the major intracerebral source of macrophage inflammatory protein‐3α/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro

Ambrosini, Elena; Columba-Cabezas, Sandra; Serafini, Barbara; Muscella, Antonella; Aloisi, Francesca

doi:10.1002/glia.10193

Cited by 100 publications

(63 citation statements)

References 47 publications

(59 reference statements)

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“…Our results confirmed the overexpression of CCL20 described in CNS during EAE [13], with highest transcript levels during onset and early acute phase. CCR6 1/1 and CCR6 À/À mice showed similar increases in transcript levels and expression pattern of CCL20 in CNS (Fig.…”

Section: Ccr6 Deficiency Does Not Affect Encephalitogenic Response Orsupporting

confidence: 89%

“…Studies in EAE models suggest that the chemokine CCL20 and its receptor CCR6 are involved in MS and EAE. CCL20 expression is upregulated in both the CNS and the draining LN (DLN) during clinical disease; the major intracerebral source of CCL20 is infiltrating lymphocytes at disease onset and astrocytes during relapse [13,14]. Administration of neutralizing anti-CCL20 Ab at the time of EAE induction reduces disease severity, suggesting a role for this chemokine in the sensitization phase of EAE, although adoptive transfer experiments with reactive T cells indicate that CCL20 is not necessary for the effector phase of disease [14].…”

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confidence: 99%

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CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

et al. 2009

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The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4 1 T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4 1 T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6 À/À mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3 1 cell frequency characterized CNS tissues from CCR6 À/À compared with CCR6 1/1 mice during the disease effector phase. Transfer of CCR6 1/1 Treg to CCR6 À/À mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3 1 cells and recovery of the cytokine balance in CCR6 À/À mouse CNS. Competitive assays between CCR6 1/1 and CCR6 À/À Treg adoptively transferred to CCR6 À/À mice showed impaired ability of CCR6 À/À Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4 1 Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.Key words: Chemokines . EAE/MS . Inflammation . T cells Introduction EAE is a CNS disease characterized by mononuclear cell infiltration and demyelination; it is used to study certain aspects of human MS. EAE can be induced via immunization with neural antigens such as myelin oligodendrocyte glycoprotein (MOG). The immunopathological event in EAE and MS initiates when autoreactive T cells in the systemic immune compartment are activated and cross the blood-brain barrier [1]. Re-encounter of encephalitogenic T cells with their antigen leads to reactivation and expansion of autoreactive T cells, which in turn stimulate microglia/astrocyte activity, with increased release of proinflammatory cytokines and chemokines. The action of these mediators leads to demyelination and axon degeneration [2,3]. After antigen contact, naive CD4 1 T cells differentiate into various effector-cell subsets characterized by the cytokines they produce and by their immune regulatory functions. Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites. The correct in vivo location of these cell subsets, necessary for their interaction with accessory or target cells, is regulated by [11], which are assumed to have a critical impact on MS and EAE pathogenesis [12]. St...

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Section: Ccr6 Deficiency Does Not Affect Encephalitogenic Response Orsupporting

confidence: 89%

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confidence: 99%

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

et al. 2009

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“…Previous studies have shown that the main source of CCL-20 in the CNS is TNF-a-or IL-1b-activated astrocytes (43). Moreover, CCL-20 mRNA expression is reportedly upregulated in the CNS during EAE, which is closely related to the disease severity (44).…”

Section: Discussionmentioning

confidence: 97%

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

Zhou

Sonobe

Akahori

et al. 2011

The Journal of Immunology

122

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Newly discovered IL-9–producing helper T cells (Th9) reportedly exert both aggravating and suppressive roles on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, it is still unclear whether Th9 is a distinct Th cell subset and how IL-9 functions in the CNS. In this study, we show that IL-9 is produced by naive CD4+ T cells that were stimulated with anti-CD3 and anti-CD28 Abs under the conditions of Th2-, inducible regulatory T cell-, Th17-, and Th9-polarizing conditions and that IL-9 production is significantly suppressed in the absence of IL-4, suggesting that IL-4 is critical for the induction of IL-9 by each producing cell. The IL-9 receptor complex, IL-9R and IL-2Rγ, is constitutively expressed on astrocytes. IL-9 induces astrocytes to produce CCL-20 but not other chemokines, including CCL-2, CCL-3, and CXCL-2 by astrocytes. The conditioned medium of IL-9–stimulated astrocytes induces Th17 cell migration in vitro, which is cancelled by adding anti–CCL-20 neutralizing Abs. Treating with anti–IL-9 neutralizing Abs attenuates experimental autoimmune encephalomyelitis, decreases the number of infiltrating Th17 cells, and reduces CCL-20 expression in astrocytes. These results suggest that IL-9 is produced by several Th cell subsets in the presence of IL-4 and induces CCL-20 production by astrocytes to induce the migration of Th17 cells into the CNS.

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“…However, the increased difference in migratory rates of Treg and non-Treg in the presence of a MBMEC layer hints to Treg-specific interactions with the endothelial cell layer, either due to direct cell-cell contact or due to a constitutive secretion of soluble factors by the endothelial cells. CCL20 as a soluble stimulus secreted by the MBMEC layer can be excluded since its expression is only found in epithelial cells of the choroid plexus and astrocytes during EAE relapse [20,21] but not in brain endothelium. More likely, Treg seem to have an advantage in forming stable cell-cell contacts with the brain endothelium, consistent with their higher expression of LFA-1 and CD49d, as they intensively accumulated in or on top of the endothelial cell monolayer compared to their non-regulatory counterparts.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

et al. 2010

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Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD41 Foxp31 regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.Key words: Blood-brain barrier . Brain microvascular endothelial cells . Migration . MS . Regulatory T cells Supporting Information available online IntroductionNaturally occurring CD4 1 Foxp3 1 regulatory T cells (Treg) are essential mediators of peripheral immune tolerance, regulating inflammation in the context of infection, autoimmunity, neoplasia and transplant rejection [1]. In addition to balancing immunity within lymphoid tissues, Treg enter non-lymphoid target sites of inflammation, exerting their anti-inflammatory function there [2][3][4][5]. First, regulatory as well as effector T-cell subsets have to undergo a non-lymphoid homing receptor switch after entering secondary lymphoid tissue [6]. Upon encountering specific antigens provided by dendritic cells in the T-cell area [7], the lymphocytes acquire an activated phenotype, expressing distinct surface markers of non-lymphoid homing Ã These authors contributed equally to this work. We here combined various murine and human models quantifying transmigratory capacity and locomotion to determine how constitutive, innate Treg motility translates into diapedesis across CNS endothelium. Results Murine Treg exhibit enhanced migratory capacity in vitro and in vivoWe first characterized lymph node-derived regulatory and nonregulatory T-cell subsets with regard to their expression of surface markers indicative for adhesion, migration and activation. In line with previous results for CCR6 [17], murine Treg consistently showed a significantly higher expression for all inspected markers apart from CCR7, where the higher expression was not significant (p 5 0.126), and a significantly lower e...

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Astrocytes are the major intracerebral source of macrophage inflammatory protein‐3α/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro

Cited by 100 publications

References 47 publications

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

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Astrocytes are the major intracerebral source of macrophage inflammatory protein‐3α/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro

Cited by 100 publications

References 47 publications

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

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CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues