Intestinal lysozyme controls mucosal immune response to microbiota

项目总结： 肠道潘氏细胞和一些髓系细胞分泌溶菌酶，这是一种催化裂解的糖苷水解酶 细菌细胞壁，并通过非酶区域发挥杀菌活性。该功能具有独一无二的 将溶菌酶与其他抗菌肽区分开来。肠道溶菌酶水平升高及其异位 在临床活动性肠炎条件下，可观察到结肠粘膜产生的细菌。最新研究 描述了克罗恩病(CD)患者潘氏细胞中溶菌酶的包装和分泌缺陷。 不幸的是，现有文献表明溶菌酶既有促进结肠炎的作用，也有保护结肠炎的作用。这个 人类LyZ基因位于溃疡性结肠炎(UC)危险基因的附近，并且LYZ突变的患者 出现IBD症状。尽管肠道溶菌酶与UC和CD有很强的相关性，但令人惊讶的是 对其在调节肠道微生物区系和粘膜免疫反应中的确切生理功能知之甚少。 这一认识差距的存在是由于缺乏直接研究溶菌酶在体内功能的模型。这一缺口防止了 充分认识溶菌酶在DISTIC进展和治疗中的临床意义 IBD表格。我们已经建立了几种小鼠模型来促进肠道溶菌酶的功能研究。 在生产条件不足或过剩的情况下。初步数据表明，溶菌酶缺乏会导致 某些与IBD相关的细菌种类的扩张导致的生物失调。当屏障函数急剧增加时 在这些患者中，机会性致病菌的移位增强，并加剧了结肠炎 老鼠。进一步分析发现溶菌酶敏感微生物对上皮细胞产生意想不到的影响 分化和成分，以及对粘膜免疫反应的影响。这个创新的项目 将研究溶菌酶缺陷如何影响IBD相关细菌的定植，如何对溶菌酶敏感 物种调节肠道粘膜，以及溶菌酶和细菌相互作用如何影响肠道粘膜的进展和 具有不同炎症特征的不同实验性IBD的分辨率。中心假设是 肠道溶菌酶对肠道微生物群落的调控及其对黏膜免疫反应的影响 炎性口气与IBD易感性的关系。这一假设是在初步数据的基础上提出的 和现有的文学作品。两个高度结合的目标将首先描述溶菌酶对肠道微生物区系的影响， 通过对溶菌酶敏感的微生物群调节粘膜的动态平衡和炎症，然后 检测溶菌酶缺陷在不同免疫学类型实验性结肠炎中的作用 简介，特别致力于了解2型免疫信号在这些过程中的作用。 这个MPI项目是建立在两个PIS在实验中互补和不可或缺的专业知识上的 结肠炎、粘膜免疫学、生物质研究、遗传学和肠上皮生物学。该项目利用 严格的遗传方法，预计将产生对肠道的独特和与疾病相关的见解 溶菌酶及其对微生物区系、粘膜免疫学和IBD的影响。

PROJECT SUMMARY: Intestinal Paneth cells and some myeloid cells secrete lysozyme, a glycoside hydrolase that catalytically cleaves bacterial cell-wall as well as exerts bactericidal activity through a non-enzymatic domain. This feature uniquely distinguishes lysozyme from other antimicrobial peptides. Elevated levels of intestinal lysozyme and its ectopic production by colonic mucosa are observed in clinically active intestinal inflammation conditions. Recent studies described defective lysozyme packaging and secretion in Paneth cells of Crohn’s disease (CD) patients. Unfortunately, existing literature suggested both a colitis-promoting and a colitis-protective role of lysozyme. The human LYZ gene is located in the vicinity of an Ulcerative Colitis (UC) risk locus, and patients with LYZ mutations exhibit IBD symptoms. Despite of these strong associations of intestinal lysozyme with UC and CD, surprisingly little is known about its exact physiological functions in regulating gut microbiota and mucosal immune response. This knowledge gap exists due to a lack of models for direct study of lysozyme in vivo function. This gap prevents us from fully understanding the clinical implication of lysozyme in the progression and management of distinct IBD forms. We have developed several mouse models to facilitate functional investigation of intestinal lysozyme under its deficient or over production conditions. Preliminary data suggest that lysozyme deficiency leads to a dysbiosis with an expansion in certain IBD-related bacterial species. When barrier function is acutely compromised, there is an enhanced translocation of opportunistic pathobionts and exacerbated colitis in these mice. Further analyses uncovered lysozyme sensitive microbes, an unexpected impact on epithelial cell differentiation and composition, as well as an influence on the mucosal immune response. This innovative project will investigate how lysozyme defects affect the colonization of IBD-related bacteria, how lysozyme-sensitive species modulate gut mucosa, and how lysozyme and bacterial interaction influences the progression and resolution of different experimental IBDs with distinct inflammatory profiles. The central hypothesis is that intestinal lysozyme modulates gut microbial community and its impact on mucosal immune responses to regulate inflammatory tone and the susceptibility of IBD. This hypothesis is formulated on the basis of preliminary data and existing literature. Two highly cohesive aims will first delineate the impact of lysozyme on gut microbiota, the regulation of mucosal homeostasis and inflammation by the lysozyme-sensitive microbiota, and will then examine the contribution of lysozyme defects to distinct forms of experimental colitis of different immunological profiles, with a particular effort devoted to understanding the role of type 2 immune signaling in these processes. This MPI project is constructed on complementary and indispensable expertise of the two PIs in experimental colitis, mucosal immunology, gnotobiotics study, genetics, and intestinal epithelial biology. The project utilizes rigorous genetic approaches and is expected to produce unique and disease-relevant insights into intestinal lysozyme and its impact on microbiota, mucosal immunology, and IBDs.