Innate immune response in adipocytes: impact for intestinal inflammation

克罗恩病的特点是肠系膜脂肪组织增加，这种现象被更好地描述为蠕动脂肪。匍匐脂肪包围炎症肠段，并表现出特异性变化，包括脂肪细胞增生、抗炎巨噬细胞增加、转定位细菌以及纤维化变化。我们之前的数据表明，克罗恩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先天信号通路触发这些特异性变化。因此，我们假设克罗恩病的肠系膜脂肪起第二屏障的作用，因此具有保护作用。我们提出这一建议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部分将致力于表征人类样本的形态学、趋化因子和脂肪酸谱，作为单核细胞浸润的可能触发因素。此外，为了提供局部环境的深入表征，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。这些数据将有助于确定脂肪组织中特定疾病的变化。基于我们之前的数据，我们提出肠系膜脂肪中先天免疫系统的激活是观察到的变化的关键机制。因此，我们产生了脂肪细胞特异性的Myd88-/-小鼠。在B部分，这些动物将在急性和慢性肠道炎症模型中进行检查，肠系膜脂肪的相关变化将根据人体组织中分析的终点进行分析。这些实验将为脂肪细胞是否对观察到的变化至关重要提供证据。在C部分，互补的体外共培养实验将有助于将患者队列的描述性发现与动物模型的功能数据联系起来。通过这些研究，我们旨在确定脂肪细胞先天免疫反应的激活对克罗恩病疾病特征变化的影响。这些新的机制见解将允许未来隔间特定治疗策略的发展。

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.