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GSE51707
Mus musculus
12 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38-controlled transcripts comprising female- and male-specific gene modules, with greater p38 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS
Publication Title
Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 15 Downloadable Samples
Illumina HiSeq 2500
Description
Previously, using a forward genetic approach we identified B. burgdorferi arthritis-associated locus 1 (Bbaa1), a quantitative trait locus on Chr4, which physically encompasses the type I IFN gene cluster and regulates Lyme arthritis through heightened type I IFN production. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the Bbaa1 interval, and RNA-seq of resident CD45- joint cells from advanced interval specific recombinant congenic lines (ISRCL4 and ISRCL3) identified myostatin as uniquely upregulated in association with Bbaa1 arthritis development. Our manuscript further demonstrates that myostatin expression is linked to IFN-ß production, and in vivo inhibition of myostatin suppresses Lyme arthritis in the reduced interval Bbaa1 congenic mice, formally implicating myostatin as a novel downstream mediator of joint-specific inflammatory response to B. burgdorferi. Overall design: 22 days following infection with B. burgdorferi, mouse rear ankle joints were gently digested into single-cell suspensions and CD45 negative cells were isolated by magnetic bead separation. CD45 negative cells from both rear ankle joints of two mice were pooled for each n sample in order to increase RNA concentration for gene expression analysis (n=5 per genotype). Gene expression comparisons were made between B6 (control group) and ISRCL4/ISRCL3 congenic lines.
Publication Title
Genetic Control of Lyme Arthritis by <i>Borrelia burgdorferi</i> Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The prevalence of some autoimmune diseases (AID) is greater in females compared with males, notwithstanding that disease severity is often greater in males. The reason for this sexual dimorphism (SD) is unknown, but may reflect negative selection of Y chromosome (ChrY) bearing sperm during spermatogenesis or male fetuses early in the course of conception/pregnancy. Previously, we showed that the SD in experimental autoimmune encephalomyelitis (EAE) is associated with copy number variation (CNV) in ChrY multicopy genes. Here, we test the hypothesis that CNV in ChrY multicopy genes influences the paternal parent-of-origin effect on EAE susceptibility in female mice. We show that C57BL/6J consomic strains of mice possessing an identical ChrX and CNV in ChrY multicopy genes exhibit a female biased sex-ratio and sperm head abnormalities, consistent with X-Y intragenomic conflict arising from an imbalance in CNV between homologous ChrX:ChrY multicopy genes. These males also display paternal transmission of EAE to female offspring and differential loading of miRNAs within the sperm nucleus. These findings provide evidence for a genetic mechanism at the level of the male gamete that contributes to the SD in EAE and paternal parent-of-origin effects in female mice, raising the possibility that a similar mechanism may contribute to the SD in MS.
Publication Title
Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 36 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J background, we show that susceptibility to two diverse animal models of autoimmune disease, including experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. In the B6 background, ChrY possesses gene regulatory properties that impact both genome-wide gene expression and the presence of alternative splice variants in pathogenic CD4+ T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY-mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4+ T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly upregulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Moreover, in humans, an analysis of the CD4+ T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, these data establish ChrY as a member of the regulatory genome in mammals due to its ability to regulate gene expression and alternative splicing in immune cells linked to disease.
Publication Title
The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Gene expression profile of joint tissue from C3H and interval specific congenic mouse lines (ISCL) following infection with Borrelia burgdorferi
Publication Title
Interval-specific congenic lines reveal quantitative trait Loci with penetrant lyme arthritis phenotypes on chromosomes 5, 11, and 12.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J background, we show that susceptibility to two diverse animal models of autoimmune disease, including experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. In the B6 background, ChrY possesses gene regulatory properties that impact both genome-wide gene expression and the presence of alternative splice variants in pathogenic CD4+ T cells compared to CD4+ T cells. An inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly upregulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy and the ChrY genetic element exerting regulatory properties. Thus, these data establish ChrY as a member of the regulatory genome in mammals due to its ability to regulate gene expression and alternative splicing in immune cells linked to disease.
Publication Title
The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Histamine H3 receptor (Hrh3/H3R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H3R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H3R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H3RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H3R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H3R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.
Publication Title
Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
IL-6, a proinflammtory cytokine produced by antigen presenting cells and non-hematopoietic cells in response to external stimuli, acts as an important bridge between the innate and adaptive immune responses. IL-6 together with IL-4 can promote Th2 polarization, while in combination with TGFbeta mediates Th17 differentiation. We examined early changes in gene expression in mouse CD4+ T cells induced by IL-6.
Publication Title
The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.
Sample Metadata Fields
No sample metadata fields
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