Distinct mast cell responses in male and female SJL mice underlie sex dimorphic EAE susceptibility
Distinct mast cell responses in male and female SJL mice underlie sex dimorphic EAE susceptibility
批准号:
10176381
负责人:
Melissa A Brown
金额:
$49.89万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-14 至 2022-06-30
关键词:
AcuteAffectAge of OnsetAllergicAllergic DiseaseAllergic inflammationAndrogen ReceptorAndrogensAntigen ReceptorsAntigen-Presenting CellsAutoimmune DiseasesCD80 geneCD86 geneCNS autoimmune diseaseCell Differentiation processCell physiologyCellsCharacteristicsChromatinClinicalCuesDataDefectDemyelinating DiseasesDendritic CellsDevelopmentDiseaseDisease susceptibilityEpigenetic ProcessExhibitsExperimental Autoimmune EncephalomyelitisFemaleFour Core GenotypesGene ExpressionGene TargetingGenesGonadal Steroid HormonesHormonalImmune mediated destructionImmune responseImmunityImmunizationImmunizeIncidenceInflammatoryInterleukin-13Interleukin-2Interleukin-4Interleukin-5Interleukin-9KineticsLymphoid CellMHC Class II GenesMediatingMemoryMeningealModelingMolecularMolecular TargetMultiple SclerosisMusMyelinNerveNeurologicNeuronsPTPRC genePathologicPatternPeripheralPlayPredispositionProductionProstaglandin D2Proto-Oncogene Protein c-kitReceptor SignalingRelapseReporterRoleSJL MouseSex BiasSex ChromosomesSex DifferencesSignal TransductionSourceStructureT-LymphocyteTNFSF4 geneTestingTestosteroneTh2 CellsTimeTissuesWomancellular targetingcytokineexperimental studygene functionhelminth infectionhistone modificationhuman diseasein vivolipid mediatormalemast cellmouse modelmutantreceptorreceptor expressionresponsesexsexual dimorphism
中文摘要
摘要
女性更容易患上许多自身免疫性疾病。多发性硬化症(MS)患者不仅有
发病率增加3-4倍,但在平均发病年龄上存在性别差异
和临床病程。然而,这种性别二型性的细胞和分子基础仍然存在。
未定义。SJL多发性硬化症小鼠模型概括了这些差异,雌性小鼠表现出更高
与男性同龄人相比,他们的发病率、更严重的疾病以及更一致的复发-缓解模式。
这种疾病易感性的差异与定性上不同的抗髓鞘Th细胞因子相对应
回应。虽然女性会产生以Th1/Th17为主的促炎反应,但
男性是Th2偏斜和非致病的。在本申请中,我们提供了2型先天淋巴组织的证据
细胞(ILC2s)发挥男性特有的保护作用。在过敏性呼吸道模型中最好的研究,ILC2是c-kit+
并且是通过产生IL-13诱导Th2免疫所必需的。我们认为肥大细胞的激活
在雄性小鼠中免疫可诱导产生ILC2激活因子,如IL-33,促进ILC2
功能性。女性不能产生强大的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
IL33仅在男性来源的细胞中表达,尽管女性来源的肥大细胞表达等同的雄激素受体
细胞。这些数据提示了睾丸激素的细胞和分子靶点,并确定了
睾酮在中枢神经系统自身免疫性疾病中的保护作用。
具体目标1:确定IL-33的表达动力学、细胞来源(S)及其对
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
这些实验将确定表达IL-33的细胞,以及它产生的时间和地点。
具体目标2:确定睾酮如何影响IL-33和其他因素的表达
调整性二态EAE的保护。将评估IL-33基因在小鼠中的表达
睾酮或雄激素受体(AR)拮抗剂。我们将询问睾丸素是否会在
导致染色质可及性改变的Il33基因座。其他AR靶基因也将被检测。
特异性目标3:探讨性别决定基因在ILC2和肥大细胞功能中的作用
EAE。不受激素影响的性染色体对ILC2和肥大细胞的潜在作用
基因的表达和功能将使用四个核心基因的小鼠进行检测。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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海外基金