IL-3 promotes the development of experimental autoimmune encephalitis

Renner, Karl; Hellerbrand, Sonja; Hermann, Fabian; Riedhammer, Christine; Talke, Yvonne; Schiechl, Gabriela; Gómez, Manuel R.; Kutzi, Simone; Halbritter, Dagmar; Goebel, Nicole; Brühl, Hilke; Weissert, Robert; Mack, Matthias

doi:10.1172/jci.insight.87157

Cited by 39 publications

(38 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cx47KO mice showed also higher expression of FasL, which regulates T-cell functions, activates the caspase cascade and is present on glial cells in chronic MS plaques (Dowling et al, 1996;Volpe, Sambucci, Battistini, & Borsellino, 2016). Moreover, IL-2, IL-3, and IL3-beta, involved in MS pathogenesis (Renner et al, 2016;Zandian et al, 2011), showed persistent elevation at 12 dpi in Cx47KO in contrast to WT EAE mice.…”

Section: Discussionmentioning

confidence: 92%

“…Cx47KO mice showed also higher expression of FasL, which regulates T‐cell functions, activates the caspase cascade and is present on glial cells in chronic MS plaques (Dowling et al, ; Volpe, Sambucci, Battistini, & Borsellino, ). Moreover, IL‐2, IL‐3, and IL3‐beta, involved in MS pathogenesis (Renner et al, ; Zandian et al, ), showed persistent elevation at 12 dpi in Cx47KO in contrast to WT EAE mice. Finally, CCL2 produced by activated astrocytes (Rothhammer & Quintana, ) is significantly upregulated in Cx47KO EAE mice at 7 dpi, before the disruption of BBB/BSCB (Aubé et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Papaneophytou

Georgiou

Karaiskos

et al. 2018

Glia

View full text Add to dashboard Cite

Gap junctions (GJs) coupling oligodendrocytes to astrocytes and to other oligodendrocytes are formed mainly by connexin47 (Cx47) and a smaller portion by connexin32 (Cx32). Mutations in both connexins cause inherited demyelinating disorders, but their expression is also disrupted in multiple sclerosis (MS). To clarify whether the loss of either Cx47 or Cx32 could modify the outcome of inflammation and myelin loss, we induced experimental autoimmune encephalomyelitis (EAE) in fully backcrossed Cx32 knockout (KO) and Cx47KO mice and compared their outcome with wild type (WT, C57BI/6 N) mice. Cx47KO EAE mice developed the most severe phenotype assessed by clinical scores and behavioral testing, followed by Cx32KO and WT mice. Cx47KO more than Cx32KO EAE mice developed more microglial activation, myelin, and axonal loss than did WT mice. Oligodendrocyte apoptosis and precursor proliferation was also higher in Cx47KO than in Cx32KO or WT EAE mice. Similarly, blood‐spinal cord barrier (BSCB) disruption and inflammatory infiltrates of macrophages, T‐ and B‐cells were more severe in Cx47KO than either Cx32KO or WT EAE groups. Finally, expression profiling revealed that several proinflammatory cytokines were higher at the peak of inflammation in the Cx47KO mice and persisted at later stages of EAE in contrast to reduction of their levels in WT EAE mice. Thus, loss of oligodendrocyte GJs aggravates BSCB disruption and inflammatory myelin loss, likely due to dysregulation of proinflammatory cytokines. This mechanism may play an important role in MS brain with reduced connexin expression, as well as in patients with inherited mutations in oligodendrocyte connexins and secondary inflammation.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Papaneophytou

Georgiou

Karaiskos

et al. 2018

Glia

View full text Add to dashboard Cite

show abstract

“…Studies on IL-3 knock-out mice showed that IL-3 has minor nonredundant effects on hematopoiesis, but plays a significant role in anti-parasite immunity through its action on mast cells and basophils [46, 53–56]. There is increasing interest in this cytokine given recent reports on the involvement of IL-3 in augmenting features of sepsis, systemic lupus erythematosus or the experimental autoimmune encephalomyelitis model of multiple sclerosis [57–59]. …”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

Kunnath-Velayudhan

Goldberg

Saini

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Analysis of antigen-specific CD4+ T cells in mycobacterial infections at the transcriptome level is informative but technically challenging. While several methods exist for identifying antigen-specific T cells, including intracellular cytokine staining, cell surface cytokine-capture assays, and staining with peptide:MHC-II multimers, all of these have significant technical constraints that limit their usefulness. Measurement of activation-induced expression of CD154 has been reported to detect live, antigen-specific CD4+ T cells but this approach remains underexplored, and to our knowledge has not previously been applied in mycobacteria-infected animals. Here we show that CD154 expression identifies adoptively transferred or endogenous antigen-specific CD4+ T cells induced by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. We confirmed that antigen-specific cytokine production was positively correlated with CD154 expression by CD4+ T cells from BCG-vaccinated mice, and show that high quality microarrays can be performed from RNA isolated from CD154+ cells purified by cell sorting. Analysis of microarray data demonstrated that the transcriptome of the CD4+ CD154+ cells was distinct from that of CD154− cells, and showed major enrichment of transcripts encoding multiple cytokines and pathways of cellular activation. One notable finding was the identification of a previously unrecognized subset of mycobacteria-specific CD4+ T cells characterized by the production of interleukin-3. Our results support the use of CD154 expression as a practical and reliable method to isolate live, antigen-specific CD4+ T cells for transcriptomic analysis and potentially for a range of other studies in infected or previously immunized hosts.

show abstract

“…Importantly, this event is linked to oligodendrocyte depletion and demyelinating processes [42]. The IL-3 signalling pathway, which is another significant pathway in the NDP group, may be also related to MS. Renner et al [46] exhibited that IL-3 expression in T cells was increased substantially during relapse in RR-MS patients, and an anti-IL-3 monoclonal antibody reduced disease severity in experimental autoimmune encephalomyelitis (EAE). Another over-represented pathway in the NDP group was the TNF-a signalling pathway.…”

Section: Significant Protein Complexes and Ms-related Genes In The Ndmentioning

confidence: 99%

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Pazhouhandeh

Sahraian

Siadat

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Identification of autoimmune processes and introduction of new autoantigens involved in the pathogenesis of multiple sclerosis (MS) can be helpful in the design of new drugs to prevent unresponsiveness and side effects in patients. To find significant changes, we evaluated the autoantibody repertoires in newly diagnosed relapsing-remitting MS patients (NDP) and those receiving disease-modifying therapy (RP). Through a random peptide phage library, a panel of NDP- and RP-specific peptides was identified, producing two protein data sets visualized using Gephi, based on protein--protein interactions in the STRING database. The top modules of NDP and RP networks were assessed using Enrichr. Based on the findings, a set of proteins, including ATP binding cassette subfamily C member 1 (ABCC1), neurogenic locus notch homologue protein 1 (NOTCH1), hepatocyte growth factor receptor (MET), RAF proto-oncogene serine/threonine-protein kinase (RAF1) and proto-oncogene vav (VAV1) was found in NDP and was involved in over-represented terms correlated with cell-mediated immunity and cancer. In contrast, transcription factor RelB (RELB), histone acetyltransferase p300 (EP300), acetyl-CoA carboxylase 2 (ACACB), adiponectin (ADIPOQ) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) had major contributions to viral infections and lipid metabolism as significant events in RP. According to these findings, further research is required to demonstrate the pathogenic roles of such proteins and autoantibodies targeting them in MS and to develop therapeutic agents which can ameliorate disease severity.

show abstract

IL-3 promotes the development of experimental autoimmune encephalitis

Cited by 39 publications

References 55 publications

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Contact Info

Product

Resources

About