Innate immune response in adipocytes: impact for intestinal inflammation

克罗恩氏病的特征是肠系膜脂肪组织增加，这种现象更好地描述为爬行脂肪。这种蠕动脂肪包围着发炎的肠段，表现出特殊的变化，包括脂肪细胞增殖，抗炎巨噬细胞增加，细菌移位以及纤维化改变。我们以前的数据表明，Crohns病的跨壁炎症和相关的细菌易位通过刺激肠系膜脂肪中的固有信号通路来触发这些特定的变化。因此，我们假设克罗恩病患者的肠系膜脂肪起到第二屏障的作用，因此具有保护作用。通过这项建议，我们的目的是了解这些具体发现的发展和后果。为此，我们将比较克罗恩病、溃疡性结肠炎、憩室炎和结直肠癌患者的肠系膜脂肪。工作计划的A部分将致力于描述人体样本的形态、趋化因子和脂肪酸特征，以此作为单核细胞渗透的可能触发因素。此外，为了提供对局部环境的深入描述，组织巨噬细胞将通过流式细胞术和质量细胞术(CyTOF)进行分析。这些数据将允许确定脂肪组织中特定于疾病的变化。根据我们以前的数据，我们认为肠系膜脂肪中天然免疫系统的激活是观察到的变化的关键机制。因此，我们产生了一只脂肪细胞特异性的MyD88-/-小鼠。在B部分中，这些动物将在急性和慢性肠道炎症模型中进行检查，并将根据人体组织中分析的终点分析肠系膜脂肪的相关变化。这些实验将为脂肪细胞是否对观察到的变化起关键作用提供证据。在C部分，体外共培养的补充实验将用于连接来自患者队列的描述性发现和来自动物模型的功能数据。通过这些研究，我们的目标是确定脂肪细胞中天然免疫反应的激活对克罗恩病的疾病特征变化的影响。这些新的机制洞察力将允许开发未来的隔室特定的治疗策略。

Crohns disease has been characterized by an increase of the mesenteric fat tissue, a phenomenon better described as Creeping Fat. This Creeping Fat is surrounding the inflamed intestinal segments and presents with specific changes including an adipocyte hyperplasia, an increase in anti-inflammatory macrophages, translocalizing bacteria as well as fibrotic changes. Our previous data suggest that the transmural inflammation in Crohns disease and the associated bacterial translocation triggers these specific changes by stimulating innate signaling pathways in the mesenteric fat. Hence we hypothesize that the mesenteric fat in Crohns disease functions as a second barrier and is thus protective. With this proposal we aim to understand the development and consequences of these specific findings. For this we will compare the mesenteric fat from patients with Crohns disease, ulcerative colitis, diverticulitis as well as colorectal cancer. Part A of the work program will be devoted to characterize the human samples with regard to morphology and chemokine and fatty acid profile as possible triggers for monocyte infiltration. Furthermore to provide an in depth characterization of the local milieu, tissue macrophages will be analyzed via flow cytometry as well as mass cytometry (CyTOF). These data will allow for defining disease specific changes in the adipose tissue. Based on our previous data, we propose that the activation of the innate immune system in the mesenteric fat represents the critical mechanism for the observed changes. Thus we generated an adipocyte-specific Myd88-/- mouse. In part B these animals will be examined in models of acute and chronic intestinal inflammation and the associated changes in the mesenteric fat will be analyzed with regard to the endpoints analyzed in the human tissue. These experiments will provide evidence whether or not adipocytes are critical for the observed changes. In part C complementary in vitro-co-culture experiments will serve to connect the descriptive findings from the patient cohorts and the functional data from the animal models. By these studies we aim to define the impact of the activation of the innate immune response in adipocytes for the disease-characterizing changes in Crohns disease. These novel mechanistic insights will then allow for the development of future compartment specific therapeutic strategies.