T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

Clarkson, Benjamin D.; Ling, Changying; Shi, Yejie; Harris, Melissa G.; Rayasam, Aditya; Sun, Dandan; Salamat, M. Shahriar; Kuchroo, Vijay K.; Lambris, John D.; Sándor, Mátyás; Fábry, Zsuzsanna

doi:10.1084/jem.20131377

Cited by 90 publications

(91 citation statements)

References 30 publications

(41 reference statements)

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“…4&7). Such inhibition of IL-21 could indeed be beneficial to stroke outcome as indicated in a recent report showing that T-cell production of this cytokine can induce brain injury after MCAO (Clarkson et al 2014). Additional regulatory effects observed included reduced expression of MHCII, TNF-α and IL-1β by splenic CD11b + monocytes and enhanced expression of IL-4, IL-10 and IL-33, but reduced expression of ICAM-1, CXCL10, CXCR3 and MMP-9 in the ischemic brain hemisphere (Figs.…”

Section: Discussionmentioning

confidence: 95%

Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

et al. 2014

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Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10+ B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10+ B-cells can exert therapeutic and immunoregulatory effects when injected 24 hours after MCAO induction in B-cell-sufficient male WT mice. The results demonstrated that IL-10+ B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8+CD122+ Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10+ B-cells in treating MCAO in male WT mice at a time point well beyond the ~4 h tPA treatment window, leading to the generation of a dominant IL-10+CD8+CD122+ Treg population associated with spleen preservation and reduced CNS inflammation.

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Section: Discussionmentioning

confidence: 95%

Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

et al. 2014

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“…Contrastingly IL-21 is thought to play a key role in inflammatory conditions such as diabetes, multiple sclerosis, Sjogren’s syndrome and brain injury after stroke (46–50). Previously we showed that IL-21 production in chronic infection is driven by gp130 signaling (20).…”

Section: Discussionmentioning

confidence: 99%

Cell-Intrinsic gp130 Signaling on CD4+ T Cells Shapes Long-Lasting Antiviral Immunity

Harker

Wong

Dolgoter

et al. 2015

The Journal of Immunology

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The interleukin-6 (IL-6) cytokine family utilizes the common signal transduction molecule gp130, which can mediate a diverse range of outcomes. To clarify the role of gp130 signaling in vivo during acute viral infection we infected Cd4-cre Il6stfl/fl mice, in which gp130 is conditionally ablated in T cells, with acute lymphocytic choriomeningitis virus (LCMV). We found that by day 12, but not at day 8, post infection the number of virus specific CD4+ T cells was reduced in the absence of gp130, and this was sustained for up to 2 months post infection. Additionally gp130 deficient TFH had lower expression of Maf, IL-21 and ICOS and this was accompanied by a reduction in the proportion of germinal center B cells and plasmablasts. Remarkably, two months post-infection the proportion of IgG2a/c+ memory B cells and the systemic levels of LCMV-specific IgG2 Abs were dramatically decreased, while there was a corresponding increase in IgG1+ memory B cells and virus-specific IgG1 Abs. In the same animals Gp130 deficient virus specific CD8+ T cells showed a reduced proportion of memory cells, which expressed lower levels of Tcf7, and displayed diminished recall responses on secondary infection. Mixed bone marrow chimeras revealed that the aforementioned gp130 effects on CD4+ T cells were cell-intrinsic. Overall our data show that gp130 signaling in T cells influences the quantity and quality of long lasting CD4+ T cell responses as well as CD8+ T cell and antibody mediated immunity after acute viral infection.

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“…In stroke, the use of strategies aiming to block IL-17 differentiation and maintenance, such as IL-21 68 and IL-23 69,70 as well IL-17 itself, 69,71 led to protective effects. This pathogenic effect of IL-17 could be achieved through interaction of IL-17 with IL-17Rs on astrocytes, microglia, and neurons that activates many transcriptional factors, such as NF-κB, which then induces the expression of proinflammatory cytokines (eg, IL-6, TNFα, and IL-1β), chemokines (eg, CXCL1, CCL2, CXCL2, CCL7, CCL11, and CCL20), and metalloproteinases that facilitate trafficking of leukocytes across the vascular endothelial barrier and their entry into the parenchyma (for review, see Ref.…”

Section: Role Of Il-17 In Postischemic Injurymentioning

confidence: 99%

IL-17 and Th17 Cells in Atherosclerosis

Taleb

Tedgui

Mallat

2015

ATVB

217

160

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Abstract-Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms linking this pathway to atherosclerosis, as well as a perspective on the risks and benefits of interleukin-17-targeted cytokine therapy in patients at high cardiovascular risk. ATVB in Focus Modulation of Atherosclerotic Lesions by Circulating Cells:The Translational Spectrum Taleb et al Th17 Cells and Atherosclerosis 259but is also expressed at high levels in Th17 cells and may act in an autocrine manner to maintain Th17 cells in vivo. 12 Still the absolute requirement of TGF-β for in vivo Th17 differentiation in mice has been questioned. Indeed, Th17 cells are present in the gut of TGF-β signaling-deficient mice. 13,14 Furthermore, IL-6 and IL-23 in combination with IL-1β were able to induce IL-17 production in the absence of TGF-β signaling, 14 suggesting an alternative mode for Th17 cell differentiation. In humans, initial claim that TGF-β was dispensable for human Th17 differentiation 15 was subsequently challenged by several investigators who provided convincing evidence for the importance of this factor in the human setting. [16][17][18] Additional key regulators that are involved in vascular remodeling and thus associated to cardiovascular disease have been recently identified as key regulators of Th17 differentiation. For example, nitric oxide mediates nitration of tyrosine residues in RORγt, leading to the suppression of RORγt-induced IL-17 promoter activation, which highlights a negative role for nitric oxide in Th17 differentiation.19 Salt (sodium chloride) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human Th17 cells. 20 IL-17 SignalingIL-17 receptor (IL-17R) family consists of 5 subunits. IL-17 binds to the heterodimeric receptor, IL-17RA and IL-17RC, and stimulates its signaling pathway. IL17RA is ubiquitously expressed throughout the body, resulting in pleiotropic actions of IL-17 on a wide range of cell types (for review, see Ref. 21). IL-17 binds to the receptor in homodimers (IL-17A/ IL-17A or IL-17F/IL-17F) or heterodimers (IL-17A/IL-17F) conf...

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T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

Abstract: IL-21 is a key CD4+ T cell–derived inflammatory factor that contributes to increased early ischemic tissue injury.

Cited by 90 publications

References 30 publications

Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

Cell-Intrinsic gp130 Signaling on CD4+ T Cells Shapes Long-Lasting Antiviral Immunity

IL-17 and Th17 Cells in Atherosclerosis

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