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（BWF 1）狼疮小鼠模型中女性比男性更普遍。虽然雌激素会加重女性的疾病，但大量证据表明，雄激素在保护人类和小鼠的雄性免受狼疮侵害方面发挥着关键作用。肠道微生物群现在被认为在宿主健康和疾病中起着重要作用，微生物群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群产生重大影响，反之亦然。最近在1型糖尿病（T1 D）小鼠模型中的研究表明，微生物群和雄激素在现在被称为“microgenderome”的组织中合作，通过目前未知的机制保护雄性小鼠免受疾病的影响。然而，关于雄激素与狼疮微生物群之间的关系知之甚少。在初步研究中，我们发现成熟的雌性和雄性BWF 1小鼠之间的微生物群组成和代谢组学特征显著不同，将雄性微生物群转移到雌性BWF 1小鼠可以保护雌性受体免受疾病的影响，并显着提高存活率。这些数据表明，男性环境通过改变微生物群组成和/或代谢组来赋予微生物群保护特性。已经发现来自大肠杆菌的metabolic直接和通过DC诱导Treg分化。肠道CD 103+树突状细胞（CD 103 DC）是高度致耐受性的，并在外周产生调节性T细胞，可以控制全身免疫应答。我们的初步数据显示了CD 103 DC功能的性别差异，以及雄性BWF 1小鼠对CD 103+细胞的保护需求，这强烈支持了CD 103 DC作为雄性肠道微生物群和免疫应答之间的关键联系的观点，因此，可能在保护BWF 1雄性小鼠免受疾病侵害方面发挥重要作用。此外，对微生物群代谢组的初步分析已经确定了一种代谢物，该代谢物在雄性BWF 1小鼠中增加，可能影响CD 103 DC功能。因此，我们假设雄激素修饰的男性微生物群及其代谢产物通过肠道CD 103 DC起作用来保护免受狼疮的侵害。将通过以下方式在狼疮易感BWF 1小鼠中解决这一新假设：1）检查雄激素对肠道微生物群及其代谢物的影响; 2）探索雄性微生物群及其代谢物在保护免受疾病中的作用;以及3）确定CD 103 DC在雄性微生物群介导的保护免受疾病中的作用。拟议的项目将填补我们对雄激素-肠道微生物群关系在免疫调节和狼疮中的作用的知识空白，并将导致开发使用微生物群和/或其代谢物治疗狼疮和其他自身免疫性疾病的新型治疗策略。

 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.