我们最新研究发现非可控炎症中存在一群非M1非M2巨噬细胞,它同时高表达M1和M2的特异性基因，我们将该群巨噬细胞称为M3。并发现Gαi蛋白家族和HIF1α信号通路对巨噬细胞表型转化具有重要的调控作用，巨噬细胞特异性Gαi2敲除小鼠在6-8周龄出现炎性肠息肉的表型，慢性应激可以促进该良性增生在第11周龄发展为结肠癌，具体机制未明。慢性应激可通过脑-肠轴对肠道免疫发挥重要调控作用。本项目进一步研究：1）M3巨噬细胞在慢性非可控炎症中的作用及M3巨噬细胞的来源。2）慢性应激状态下脑-肠轴的ACh和5-HT及其不同亚型受体对巨噬细胞Gαi蛋白和HIF1α表达的调控作用，阐明M3巨噬细胞诱导非可控炎症的网络关键节点，解析脑-肠轴反馈调控环路。3）慢性非可控性炎症促进结肠起始细胞形成的分子机制，重点研究LTs-IKKα-E2F1-APOBEC3B、HIF-NF-κB-Wnt、PKMζ-Hipoo-YAP-β-catenin、IL6-STAT3等信号在诱导正常结肠上皮细胞去分化中的作用及其分子机制，为探索炎癌转化的调控网络关键节点、发现肿瘤防治新靶点奠定理论基础和实验依据。

Previously we have discovered a new subtype of macrophage which expresses specific markers of M1 and M2. This population of macrophage doesn't fit into the M1/M2 classification and we call it 'M3'. Besides, we have found the pivotal role of Gαi family and HIF1α signaling in mediating macrophage polarization, macrophage-specific deletion of Gαi2 mice suffered from intestinal inflammatory polyp at 6-8 week age, which could be exacerbated into colorectal cancer by chronic stress. However, the definite mechanisms are not well understood. Chronic stress could regulate gastrointestinal immunity by brain-gut axis. In this renewing project, we will 1) Study of the function and orgin of M3 macrophage. 2) illustrate the regulation mechanisms of ACh, 5-HT and their receptors in the expression of Gαi and HIF1α in macrophages, clarify the critical node in M3 induced nonresolving inflammation, and analysis brain-gut axis reflect. 3) illustrate the molecular mechanisms of colorectal caner initiating by nonresolving inflammation, we will focus on LTs-IKKα-E2F1-APOBEC3B、HIF-NF-κB-Wnt、IL6-STAT3、PKMζ-Hipoo-YAP-β-catenin and other signaling in triggering normal colorectal epithelium cell dedifferentiation, in order to explore the critical node in inflammation-cancer transformation and discover new targets for cancer treatments.