树突状细胞p38α信号通路在维持肠道免疫稳态及肠炎和肠炎相关结肠癌发生发展中的机制研究

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory intestinal disease, which does not have a cure. IBD is an important risk factor for the development of colitis-associated cancer (CAC). To better prevent and treat these diseases, it is essential to study the pathogenesis of IBD and CAC. The dysregulation of host intestinal immune responses is tightly linked to the pathogenesis of IBD; however, the cellular and molecular mechanisms by which the host immune system controls IBD development still remains poorly defined. Our recently published study has shed light on the essential roles of p38α signaling pathway in dendritic cells (DCs) in regulating intestinal immune homeostasis under non-inflammatory conditions. In this application, we will utilize multiple genetic mouse models including DC-specific deletion of p38α, the dextran sulphate sodium (DSS)-induced model of acute colitis, and the carcinogen azoxymethane/DSS-induced CAC model to determine whether DC-mediated p38α signaling mechanistically influences IBD and CAC pathogenesis through the regulation of type 1 regulatory T (Tr1) cell differentiation, microbiota landscape, and/or intestinal epithelial cell function. Completion of these studies will break new ground in our understanding of the contributions of p38α signaling and intestinal bacteria in IBD and CAC pathogenesis. Furthermore, findings could potentially be translated into much needed treatment strategies for these diseases.

炎症性肠病（IBD）是一类慢性肠道炎性疾病，易复发且难治愈，是肠炎相关结肠癌（CAC）的重要危险因素，进一步揭示其发病机制对于更好地防治IBD和CAC有重要意义。目前认为宿主肠道免疫功能失调与IBD发病密切相关，但是对调节肠道免疫功能的细胞和分子机制仍不清楚。本申请人近期研究表明在非炎性条件下树突状细胞（DC）p38α信号通路在调节肠道免疫稳态中起关键作用。本项目将以包括DC p38α特异性基因敲除鼠在内的多种基因敲除鼠为研究对象，应用DSS诱导的急性肠炎和AOM/DSS诱导的CAC模型，探讨肠道DC p38α信号通路在调节Tr1细胞分化、与肠道菌群或肠道上皮细胞相互作用及其在IBD和CAC中的作用机制。本项目首次将肠道DC p38α信号通路与Tr1细胞分化、肠道菌群的功能及IBD和CAC联系起来，研究成果将为以p38α信号通路及肠道微生态系统为靶点的IBD及CAC的临床治疗奠定理论基础。

炎症性肠病（IBD）是一类慢性肠道炎性疾病，易复发且难治愈，是肠炎相关结肠癌（CACRC）的重要危险因素，进一步揭示其发病机制对于更好地防治IBD和CACRC有重要意义。目前认为宿主肠道免疫功能失调与IBD发病密切相关，但是对调节肠道免疫功能的细胞和分子机制仍不清楚。本项目在执行过程中，研究了树突状细胞（DC）p38α信号通路在葡聚糖硫酸钠（DSS）诱导的肠炎以及CACRC中的作用，并深入阐明了DC中p38α调控IL-27表达以及介导I型调节型T（Tr1）细胞分化的机制，此外还研究了DC p38α在银屑病和哮喘中的作用。我们的研究发现：（1）DC p38α的缺失通过促进Tr1细胞的分化抑制DSS诱导的肠炎与CACRC的发病；（2）肠道DC p38α对Tr1细胞的调节作用是IL-27依赖性的；（3）肠道cDC1而非cDC2中p38α的缺失通过上调IL-27的表达促进Tr1细胞的分化；（4）急性肠炎中DC p38α依赖性的IL-27还能调控3型天然淋巴样细胞IL-22的产生与肠道上皮黏膜屏障功能；（5）DC中p38α的缺失通过上调TAK1-MEKK4/7-JNK-c-Jun信号轴促进IL-27的表达；（6）皮肤朗格汉斯细胞而不是真皮DC中p38α的缺失通过抑制γδ T细胞和Th17细胞的分化介导银屑病的发生发展；（7）肺部DC p38α以及相关分子FAS对过敏性哮喘具有重要的调节作用。通过这些研究，本项目阐明了DC p38α信号通路在肠炎和CACRC发生发展中的作用以及肠道DC调控Tr1细胞分化、DC中p38α调控IL-27表达的分子机制，为以p38α为靶点的IBD以及CACRC的细胞特异性治疗提供理论依据。