Distinct mast cell responses in male and female SJL mice underlie sex dimorphic EAE susceptibility

雄性和雌性 SJL 小鼠不同的肥大细胞反应是性别二态性 EAE 易感性的基础

• 批准号: 10176381
• 负责人: Melissa A Brown
• 金额: $ 49.89万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176381
• 关键词: Acute; Affect; Age of Onset; Allergic; Allergic Disease; Allergic inflammation; Androgen Receptor; Androgens; Antigen Receptors; Antigen-Presenting Cells; Autoimmune Diseases; CD80 gene; CD86 gene; CNS autoimmune disease; Cell Differentiation process; Cell physiology; Cells; Characteristics; Chromatin; Clinical; Cues; Data; Defect; Demyelinating Diseases; Dendritic Cells; Development; Disease; Disease susceptibility; Epigenetic Process; Exhibits; Experimental Autoimmune Encephalomyelitis; Female; Four Core Genotypes; Gene Expression; Gene Targeting; Genes; Gonadal Steroid Hormones; Hormonal; Immune mediated destruction; Immune response; Immunity; Immunization; Immunize; Incidence; Inflammatory; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-9; Kinetics; Lymphoid Cell; MHC Class II Genes; Mediating; Memory; Meningeal; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Mus; Myelin; Nerve; Neurologic; Neurons; PTPRC gene; Pathologic; Pattern; Peripheral; Play; Predisposition; Production; Prostaglandin D2; Proto-Oncogene Protein c-kit; Receptor Signaling; Relapse; Reporter; Role; SJL Mouse; Sex Bias; Sex Chromosomes; Sex Differences; Signal Transduction; Source; Structure; T-Lymphocyte; TNFSF4 gene; Testing; Testosterone; Th2 Cells; Time; Tissues; Woman; cellular targeting; cytokine; experimental study; gene function; helminth infection; histone modification; human disease; in vivo; lipid mediator; male; mast cell; mouse model; mutant; receptor; receptor expression; response; sex; sexual dimorphism

Abstract Females are more to susceptible many autoimmune diseases. In multiple sclerosis (MS), not only is there a 3-4 fold increase in disease incidence, but there are sex-determined differences in the average age of onset and clinical course. Yet the cellular and molecular underpinnings of this sex-dimorphism have remained undefined. The SJL mouse model of MS recapitulates these differences in that female mice exhibit higher incidence, more severe disease, and a more consistent relapsing-remitting pattern than their male counterparts. This difference in disease susceptibility corresponds to qualitatively distinct anti-myelin Th cell cytokine responses. Whereas females generate pro-inflammatory Th1/Th17-dominant responses, the response in males is Th2-skewed and non-pathogenic. In this application we provide evidence that type 2 innate lymphoid cells (ILC2s) exert a male-specific protective influence. Best studied in allergic airway models, ILC2s are c-kit+ and are essential for inducing Th2 immunity through production of IL-13. We propose that mast cell activation in immunized in male mice elicits production of ILC2 activating factors such as IL-33 that promote ILC2 functionality. The inability to generate a robust IL-33 response in females leads to a functional deficit in ILC2 activity. Mast cells (c-kit+ FcεR1+) are one important source of IL-33 in vivo and testosterone directly induces Il33 exclusively in male-derived cells, despite equivalent androgen receptor expression by female-derived mast cells. These data suggest a cellular and molecular target of testosterone and identify a potential mechanism of action for testosterone-mediated protection in CNS autoimmune disease. Specific Aim 1: Determine the IL-33 expression kinetics, cellular source (s) and its requirement for protection in immunized male mice. Using IL-33- reporter mice (Il33Cit/+) or IL-33-deficient mice (Il33Cit/Cit (Il33-deficient) these experiments will define the IL-33-expressing cells, when and where it is produced. Specific Aim 2: Determine how testosterone influences the expression of IL-33 and other factors that regulate sex-dimorphic EAE protection. IL-33 gene expression will be evaluated in mice treated with testosterone or androgen receptor (AR) antagonists. We will ask if testosterone induces epigenetic changes at the Il33 locus conferring changes in chromatin accessibility. Other AR target genes will also be examined. Specific Aim 3: Explore the contributions of sex determining genes on ILC2 and mast cell function in EAE. The potential effect of sex chromosomes independent of hormonal influences on ILC2 and mast cell gene expression and function will be examined using four core genotype mice.

抽象的 女性更容易患多种自身免疫性疾病。在多发性硬化症 (MS) 中，不仅存在 发病率增加 3-4 倍，但平均发病年龄存在性别差异 和临床过程。然而，这种性别二态性的细胞和分子基础仍然存在 不明确的。 MS 的 SJL 小鼠模型概括了这些差异，雌性小鼠表现出更高的 与男性相比，其发病率更高，疾病更严重，并且复发缓解模式更一致。 这种疾病易感性的差异对应于性质不同的抗髓磷脂 Th 细胞细胞因子 回应。尽管女性会产生以 Th1/Th17 为主的促炎反应，但 男性为Th2偏向且非致病性。在本申请中，我们提供的证据表明 2 型先天淋巴 细胞（ILC2）发挥男性特有的保护作用。 ILC2 是 c-kit+，在过敏性气道模型中得到了充分研究 对于通过产生 IL-13 诱导 Th2 免疫至关重要。我们建议肥大细胞激活 雄性小鼠免疫后可引发 ILC2 激活因子的产生，例如促进 ILC2 的 IL-33 功能。女性无法产生强大的 IL-33 反应，导致 ILC2 功能缺陷 活动。肥大细胞（c-kit+ FcεR1+）是体内IL-33的重要来源之一，睾酮直接诱导 尽管雌性肥大表达了同等的雄激素受体，但 Il33 只存在于雄性细胞中 细胞。这些数据表明睾酮的细胞和分子靶标，并确定了潜在的机制 睾酮介导的中枢神经系统自身免疫性疾病保护作用。 具体目标 1：确定 IL-33 表达动力学、细胞来源及其要求 对免疫雄性小鼠的保护作用。使用IL-33-报告小鼠（Il33Cit/+）或IL-33缺陷小鼠（Il33Cit/Cit （IL33 缺陷）这些实验将确定表达 IL-33 的细胞及其产生的时间和地点。 具体目标 2：确定睾酮如何影响 IL-33 和其他因素的表达 调节性别二态性 EAE 保护。将在用以下药物治疗的小鼠中评估 IL-33 基因表达： 睾酮或雄激素受体 (AR) 拮抗剂。我们将询问睾酮是否会引起表观遗传变化 Il33 位点导致染色质可及性发生变化。其他 AR 靶基因也将被检查。 具体目标 3：探索性别决定基因对 ILC2 和肥大细胞功能的贡献 EAE。独立于激素影响的性染色体对 ILC2 和肥大细胞的潜在影响 将使用四只核心基因型小鼠检查基因表达和功能。