Sex-dependent colonic microbiome and host’s transcriptomics profiles in a murine model of multiple sclerosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289817 | GEO | 2026/05/15
REPOSITORIES: GEO
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Project description:Multiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, we address sex differences in neurodegenerative mechanisms focusing on the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE). RNA sequencing of neurons in cerebral cortex during EAE showed robust differential gene expression in male EAE mice compared to male healthy, age-matched, control mice. In contrast, there were few differences in female EAE mice compared to female controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male EAE mice demonstrated decreased oxygen consumption rates during respirometry assays. Together, cortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men.
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Project description:Multiple sclerosis (MS) exhibits a sex difference with the female to male bias nearly 3:1. This may be due to differences in sex hormones, sex chromosomes, or both. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Females have two copies of Kdm6a, while males have one copy. Microglia play a key role in the neuropathology of MS. Thus, Kdm6a was selectively deleted in microglia in the MS model, experimental autoimmune encephalomyelitis (EAE), to determine the effect on microglia, neuropathology, and clinical disease. Deletion of the X chromosome gene Kdm6a in microglia ameliorated EAE in females. The transcriptome in microglia Kdm6a knockout mice compared to wild type showed downregulation of disease-associated microglia (DAM) markers and upregulation of resting microglia markers. Gene ontology analyses demonstrated that selective deletion of Kdm6a in microglia caused reversal of the transcriptome changes induced by EAE. In contrast to effects in female mice, selective deletion of Kdm6a in microglia of male mice had no effect on EAE. To complement findings using genetic knockouts, pharmacologic blocking of Kdm6a was done using metformin. Metformin treatment, compared to vehicle, ameliorated EAE in females, with microglia histologically and transcriptionally similar to those from healthy controls. Further in translation, analyses of microglia transcriptomes in MS and healthy controls suggested that blocking Kdm6a may be a novel strategy to target disease-associated microglia in MS women.
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Project description:Multiple sclerosis (MS) exhibits a sex difference with the female to male bias nearly 3:1. This may be due to differences in sex hormones, sex chromosomes, or both. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Females have two copies of Kdm6a, while males have one copy. Microglia play a key role in the neuropathology of MS. Thus, Kdm6a was selectively deleted in microglia in the MS model, experimental autoimmune encephalomyelitis (EAE), to determine the effect on microglia, neuropathology, and clinical disease. Deletion of the X chromosome gene Kdm6a in microglia ameliorated EAE in females. The transcriptome in microglia Kdm6a knockout mice compared to wild type showed downregulation of disease-associated microglia (DAM) markers and upregulation of resting microglia markers. Gene ontology analyses demonstrated that selective deletion of Kdm6a in microglia caused reversal of the transcriptome changes induced by EAE. In contrast to effects in female mice, selective deletion of Kdm6a in microglia of male mice had no effect on EAE. To complement findings using genetic knockouts, pharmacologic blocking of Kdm6a was done using metformin. Metformin treatment, compared to vehicle, ameliorated EAE in females, with microglia histologically and transcriptionally similar to those from healthy controls. Further in translation, analyses of microglia transcriptomes in MS and healthy controls suggested that blocking Kdm6a may be a novel strategy to target disease-associated microglia in MS women.
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2013-10-29 | E-GEOD-51707 | biostudies-arrayexpress
Project description:How autoimmunity is initiated in Multiple Sclerosis (MS) is unknown, but both genetic and environmental factors have been implicated. Female physiology is associated with a three times higher risk of MS and the ratio of woman to men diagnosed with MS has been increasing over time, suggesting that environmental factors are interacting with female sex to initiate this disease. One MS risk factor that has been increasing that interacts with female sex is obesity. Being overweight or obese as an adolescent increases one’s risk of MS by 2-fold and this risk increases if one is female. To explore how obesity and female sex interact to control T helper autoimmunity, we conducted a proteomic screen on the serum of male and female healthy weight and obese participants that were affected or not affected by MS. We found that obese individuals, regardless of disease status, exhibited a prominent upregulation of proteins in pathways associated with the damage-associated S100 protein pathway, T helper 1 (Th1), IL-17 pathways and RIG-I/Interferon pathways and that this increase was more prominent in women. To explore the mechanisms of how female sex interacts with increased adiposity to regulate CNS autoimmunity, we modeled a diet-induced overweight (DIO) state in mice by placing animals on high fat diet for 4 weeks and then inducing experimental autoimmune encephalomyelitis (EAE), a model of MS. We found that DIO enhanced EAE severity in mice of both sexes compared to controls and this effect was more pronounced in female mice. The increased severity in the female DIO mice associated with a greater accumulation of pathogenic IFN-+IL-17+ CD4+ cells in the CNS and more severe tissue damage. Further studies of mice at steady-state revealed that DIO increased the frequency of CD44hiCD4+ T cells and enhanced the potential of naïve CD4+ T cells to produce IFN-This phenotype of higher T cell IFN-was also observed in female humans who were overweight. Furthermore, IFN-α was detected at significantly increased levels in the serum of the DIO-female compared to DIO-male or sex-matched control mice. Loss of IFN-α receptor in T cells negated the increases in Th1 inflammation and EAE severity caused by DIO in female mice. These results highlight that an overweight state may interact with female sex to selectively enhance Th1 responses and CNS autoimmunity by increasing type I and type I IFN signalling in T cells.
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Project 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 p38α 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 p38α 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 p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38α 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
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Project description:Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system (CNS) autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in effector CD4 T effector cells, but not CD4 Treg cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype-dependent, whereby high VitD: 1) was protective, 2) had no effect, and, 3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex-specific, and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation. Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype-dependent, and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.
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Project description:sex-specific role of p38-MAPK in EAE is regulated by estrogen receptor alpha; Biological sex is a critical factor in regulating immune function. A striking example of this is the higher prevalence of autoimmune diseases such as multiple sclerosis (MS) and lupus in females compared to males. While many studies have implicated the role of sex hormones such as estrogens and androgens in these sex differences, surprisingly little is known about other molecular pathways that underlie sex differences or interact with sex hormones. We have previously shown that conditional ablation of p38α MAP kinase signaling in myeloid cells (p38αCKO) was protective in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), in female but not male mice. This sex difference was dependent on the presence of sex hormones, leading us to hypothesize that the pathogenic function of p38α in EAE depends on estrogen signaling via one of the two nuclear estrogen receptors, encoded by Esr1 and Esr2. To test this hypothesis, we performed experiments with p38αCKO macrophages, which demonstrated that the effects of estradiol and p38α were independent of one another in vitro. Since many sex hormone effects are lost in vitro, we generated p38αCKO mice lacking either Esr1 or Esr2, and evaluated their EAE susceptibility in vivo. Myeloid-specific deletion of Esr1 abrogated protection in p38αCKO females, although global deletion of Esr1 and Esr2 did not. Moreover, global or myeloid-specific disruption of Esr1 unexpectedly promoted protection from EAE in p38αCKO males. Mechanistically, Esr1 deletion resulted in partial reprogramming of p38α-dependent transcriptional modules in male macrophages, in particular those regulated by TGFβ, BRD4, and SMARCA4. These results demonstrate that estrogen signaling in myeloid cells plays an important sex-specific role in programming their dependence on specific intracellular signaling pathways in the context of autoimmune disease pathogenesis, suggesting potential avenues for sex-specific therapeutics or combinatorial approaches for the treatment of such diseases.
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