组蛋白去甲基化酶JMJD1A在细菌性肠炎中对肠道保护作用的分子机制研究

We found that JMJD1A expression was upregulated in the colonic epithelial cells of WT mice and JMJD1A promoted host survive and clearance of C. rodentium in the feces after oral infection with C. rodentium. Furthermore, we also found that JMJD1A knockout mice exhibited impaired expression of CCL8 in the colon and impaired recruitment of macrophages and CD4+ T cells into the colon. In light of these results, we hypothesize that JMJD1A may protect host defense against enteric bacteria through recruiting macrophages and CD4+ T cells via upregulation of CCL8 expression. In this study, we will test this hypothesis by answering the questions as followed: Firstly, we will determine how and why the expression of JMJD1A is upregulated in the colonic epithelial cells of WT mice after C. rodentium infection; secondly, we will access effects of JMJD1A deficiency on the bacterial load, colonic injury and colonic inflammation after oral infection with C. rodentium; thirdly, we will determine how JMJD1A regulates the expression of CCL8; finally, we will examine the correlation of JMJD1A with CCL8 expression between human IBD colon specimens and nomal colon tissues. Answering these questions will help us to demonstrate the molecular mechanism of protective role of JMJD1A in C. rodentium infection, which can provide new strategy for prevention and therapy of bacterial enteritis.

我们发现感染鼠类柠檬酸杆菌后，小鼠结肠上皮细胞中JMJD1A表达上调，而且JMJD1A促进小鼠生存和粪便中鼠类柠檬酸杆菌的清除。同时，我们还发现感染鼠类柠檬酸杆菌后，与野生型小鼠相比，JMJD1A敲除小鼠表现出结肠中CCL8表达以及结肠中被募集巨噬细胞和CD4+T细胞显著减少。因此，我们提出在细菌性肠炎中JMJD1A可能通过上调CCL8表达募集巨噬细胞和CD4+T细胞对肠道起保护作用。在本课题我们将对如下科学问题进行研究：1.鼠类柠檬酸杆菌感染后结肠上皮细胞中JMJD1A表达上调的分子机制；2.JMJD1A缺失对各组织器官中鼠类柠檬酸杆菌数目、结肠损伤和结肠炎症的影响；3.JMJD1A调节CCL8表达的分子机制；4.人炎性肠炎组织样本中JMJD1A表达与CCL8表达的相关性。回答这些问题有助于我们揭示JMJD1A在细菌性肠炎中对宿主保护作用的分子机制，为细菌性肠炎的防治提供新策略。

组蛋白去甲基化酶JMJD1A能够特异性去除H3K9一甲基化和二甲基化。虽然JMJD1A在许多生理和病理性过程中的作用已被揭示，但是JMJD1A在宿主防御鼠类柠檬酸杆菌感染中的作用仍不清楚。在本研究中,我们发现鼠类柠檬酸杆菌感染通过激活STAT1-IRF-1信号通路，在转录水平上诱导JMJD1A表达。此外，JMJD1A促进了鼠类柠檬酸杆菌清除和宿主存活，并限制了鼠类柠檬酸杆菌感染后的系统性扩散。在鼠类柠檬酸杆菌感染后，JMJD1A-/-小鼠结肠中CD4+ T细胞和巨噬细胞的数量显著减少。与此一致的是，在鼠类柠檬酸杆菌感染后，JMJD1A-/-小鼠结肠中CCL8的表达也显著减少，而CCL8负责募集CD4+ T细胞和巨噬细胞且是清除鼠类柠檬酸杆菌所必需的。此外，在鼠类柠檬酸杆菌感染后，AAV9-shJMJD1A病毒介导的JMJD1A敲低增加了鼠类柠檬酸杆菌的菌落负担，并减少了结肠中CD4+ T细胞和巨噬细胞的募集。机制上，JMJD1A与IRF-1相互作用并去除CCL8启动子上H3K9二甲基化诱导CCL8表达。总之，这些结果表明，JMJD1A至少部分是通过促进CCL8的表达增加结肠中CD4+ T细胞和巨噬细胞的募集有助于宿主防御肠道细菌感染。