爬行脂肪巨噬细胞M2极化诱导周细胞转分化在克罗恩病相关肠纤维化中的作用及机制研究

肠纤维化是克罗恩病（CD）进展过程中最常见的不可逆性病理改变。新近证实周细胞是纤维化的核心应答细胞，预实验显示周细胞在CD肠纤维化（CDAIF）肠壁中脱离血管壁迁移聚集并获得成肌纤维细胞表型，然而其调控因素尚不明确。爬行脂肪（CF）是CD的特征性表现，塑造了一个巨噬细胞（Mø）M2极化微环境，预实验显示CF内M2 Mø显著增加，体外实验显示M2 Mø条件培养基能够上调周细胞表面受体的表达。据此我们推测：爬行脂肪Mø M2极化可诱导周细胞转分化，从而参与CDAIF的发生发展。本项目拟验证：①CF诱导Mø M2极化，通过激活周细胞表面受体PDGFRβ/IL-36R及下游的NCK1/2、MyD88/IRAK4等信号调控周细胞转分化。②采用周细胞荧光报告小鼠肠纤维化模型验证周细胞通过转分化参与肠纤维化的发生。本项目将为阐明CDAIF发生发展的机制提供新的实验依据，并为其有效防治提供新靶点。

Intestinal fibrosis is the common non-reversible change during the procedure of Crohn’s disease (CD) development. Pericytes has been identified to be the core response cell of fibrosis, and our previous study found that pericytes detached vessel wall, migrated and accumulated in the fibrotic intestine of CD patients, demonstrating a myofibroblast phenotype. However, the regulatory factors and potential underlying mechanism by which pericytes accelerate the progression of Crohn’s disease associated intestinal fibrosis (CDAIF) still remains unclear. The creeping fat (CF), a hallmark of CD, supplies a microenvironment for macrophages polarization to M2 macrophages. In addition, our preliminary data demonstrated that M2 macrophages was highly increased in CF, and the conditioned medium of M2 macrophages could upregulate the expression of receptors in the pericytes membrane. Hence, we inferred that under the influence of CF, the macrophages could be polarized to assume a M2 phenotype and induce the pericytes transdifferentiation into the myofibroblasts-like cells, thus contributed to the development of CDAIF. The present study would perform following work: (1) To determine the role of CF in the induction of M2 macrophages polarization, and verify the effect of M2 macrophages in the transdifferentiation of pericytes through the activation of PDGFR β/IL-36 receptor, the membrane receptor of pericytes, and its downstream NCK1/2, MyD88/IRAK4, WNT/LRP-6 pathways; (2) To further identify that pericytes transdifferentiation contributed to the pathogenesis of intestinal fibrosis by use of the fluorescent-labelled pericytes in mice intestinal fibrotic model. The study will supply a new theory basis to clarify the pathogenesis of CDAIF, and else provide new targets for prevention and treatment.