Interplay of androgens, microbiota and immunoregulation in lupus

 描述(由申请人提供)：重新提交系统性红斑狼疮(SLE)在人类和(NZBxNZW)F1(BWF1)狼疮小鼠模型中女性比男性更常见。虽然雌激素可以加重女性的疾病，但相当多的证据表明，在人类和小鼠中，雄激素在保护男性免受狼疮的影响方面发挥着关键作用。肠道微生物区系现在被认为在宿主健康和疾病中发挥着重要作用，微生物区系失调与自身免疫性疾病的发展有关。有趣的是，雄激素可以对微生物区系产生重大影响，反之亦然。最近在1型糖尿病小鼠模型(T1D)中的研究表明，微生物区系和雄激素相互协作，通过目前未知的机制保护雄性小鼠免受疾病的侵袭。然而，狼疮中雄激素与微生物区系之间的关系却知之甚少。在初步研究中，我们发现成熟的雌性和雄性BWF1小鼠的微生物区系组成和代谢谱都有显著差异，将雄性微生物区系转移到雌性BWF1小鼠可以保护雌性受体免受疾病的侵袭，并显著提高存活率。这些数据表明，雄性环境通过改变微生物区系的组成和/或代谢物，赋予微生物区系以保护性质。已发现来自共生细菌的代谢物可以直接或通过DC诱导Treg分化。肠道CD103树突状细胞(CD103树突状细胞)具有高度的耐受性，并在外周产生调节性T细胞，控制全身免疫反应。我们的初步数据显示，在BWF1雄性小鼠中，CD103 DC的功能存在性别差异，并且需要CD103细胞进行保护，这有力地支持了CD103 DC作为雄性肠道微生物区系和免疫反应之间的关键纽带的概念，因此，可能在保护BWF1雄性小鼠免受疾病侵袭方面发挥重要作用。此外，对微生物代谢组的初步分析已经确定了一种在雄性BWF1小鼠中增加的代谢物，可能对CD103 DC功能有影响。因此，我们假设雄激素修饰的男性微生物区系及其代谢产物通过作用于肠道CD103DC来预防狼疮。这一新的假说将通过1)检测雄激素对肠道微生物区系及其代谢物的影响；2)探索男性微生物区系及其代谢物在疾病保护中的作用；以及3)确定CD103 DC在男性微生物区系介导的疾病保护中的作用，在狼疮易感性BWF1小鼠中得到解决。拟议的项目将填补我们关于雄激素-肠道微生物区系在免疫调节和狼疮中的作用的知识空白，并将导致利用微生物区系和/或其代谢物治疗狼疮和其他自身免疫性疾病的新治疗策略的开发。

 DESCRIPTION (provided by applicant): Resubmission Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans, and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females, considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota is now thought to play a major role in host health and disease, and microbiota dysbiosis is associated with development of autoimmune diseases. Interestingly, androgens can have a significant impact on the microbiota and vice versa. Recent studies in a mouse model of type 1 diabetes (T1D) suggest that the microbiota and androgens collaborate, in what is now being referred to as the "microgenderome", to protect male mice from disease via currently unknown mechanisms. However, little is known about the relationship between androgens and the microbiota in lupus. In preliminary studies, we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice, and transfer of male microbiota to female BWF1 mice protects female recipients from disease, and significantly enhances survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or metabolome. Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through DC. The gut CD103+ dendritic cells (CD103DC) are highly tolerogenic, and generate regulatory T cells in the periphery that can control systemic immune responses. Our preliminary data showing sex-based differences in CD103DC function, and the requirement for CD103+ cells for protection in male BWF1 mice strongly support the notion that CD103DC function as a critical link between the male gut microbiota and the immune response, and may, therefore, play an important role in protecting BWF1 male mice from disease. Moreover, preliminary analysis of the microbiota metabolome has identified a metabolite that is increased in male BWF1 mice that may have an impact CD103DC function. We, therefore, hypothesize that the androgen-modified male microbiota and its metabolites protect against lupus by acting through the gut CD103DC. This novel hypothesis will be addressed in lupus-prone BWF1 mice by 1) examining the impact of androgens on the gut microbiota and its metabolites; 2) exploring the role of male microbiota and its metabolites in protection from disease; and 3) determining the role that CD103DC play in male microbiota- mediated protection from disease. The proposed project will fill the gaps in our knowledge about the role of the androgen-gut microbiota relationship in immunoregulation and lupus, and will lead to the development of novel therapeutic strategies using the microbiota and/or its metabolites for the treatment of lupus and other autoimmune diseases.