Innate immune response in adipocytes: impact for intestinal inflammation

脂肪细胞的先天免疫反应：对肠道炎症的影响

• 批准号: 317046214
• 负责人: Professorin Dr. Britta Siegmund
• 金额: --
• 依托单位: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie (CBF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317046214?language=en
• 关键词: Innate; immune; response; adipocytes; impact

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.

克罗恩斯疾病的特征是肠系膜脂肪组织的增加，这种现象更好地描述为蠕动的脂肪。这种蠕动的脂肪围绕着发炎的肠片段，并带来了特定的变化，包括脂肪细胞增生，抗炎巨噬细胞的增加，易位性细菌以及纤维化变化。我们先前的数据表明，克罗恩斯疾病和相关细菌易位的透壁炎症通过刺激肠系膜脂肪中的先天信号通路来触发这些特定的变化。因此，我们假设克罗恩斯疾病中的肠系膜脂肪是第二个障碍，因此具有保护性。通过此提案，我们旨在了解这些具体发现的发展和后果。为此，我们将比较来自克罗恩斯疾病，溃疡性结肠炎，憩室炎和大肠癌的肠系膜脂肪。该工作计划的A部分将致力于表征人类样品在形态学，趋化因子和脂肪酸概况方面可能是单核细胞浸润的触发因素。此外，要提供局部环境的深入表征，将通过流式细胞仪和质量细胞仪（Cytof）分析组织巨噬细胞。这些数据将允许定义脂肪组织中疾病的特定变化。根据我们以前的数据，我们建议肠系膜脂肪中先天免疫系统的激活代表观察到的变化的关键机制。因此，我们生成了脂肪细胞特异性myd88 - / - 鼠标。在B部分中，这些动物将在急性和慢性肠道炎症的模型中进行检查，肠系膜脂肪的相关变化将在人体组织中分析的终点。这些实验将提供脂肪细胞是否对观察到的变化至关重要的证据。在C部分中，互补的体外培养实验将有助于连接患者队列中的描述性发现和动物模型的功能数据。通过这些研究，我们旨在定义脂肪细胞中先天免疫反应激活对克罗恩斯疾病的疾病特征变化的影响。然后，这些新颖的机械洞察力将允许发展未来隔间特定的治疗策略。

项目成果

Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis

• DOI: 10.1038/s41598-019-55852-x
• 发表时间: 2019-12-19
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Boettcher, Chotima;Fernandez-Zapata, Camila;Priller, Josef
• 通讯作者: Priller, Josef

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans

• DOI: 10.1016/j.cell.2019.01.041
• 发表时间: 2019-03-07
• 期刊: CELL
• 影响因子: 64.5
• 作者: Bacher, Petra;Hohnstein, Thordis;Scheffold, Alexander
• 通讯作者: Scheffold, Alexander

Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease

瘦素在获得性全身性脂肪营养不良和合并克罗恩病中诱导 TNFα 依赖性炎症

• DOI: 10.1038/s41467-019-13559-7
• 发表时间: 2019
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Ziegler J;Boettcher C;Letizia M;Cansu Y;Freise I;Rodriguez-Sillke Y;Stoyanova A;Kreis M;Asbach P;Kunkel D;Priller J;Anagnostopoulos I;Kuehl A;Miehle K;Stumvoll M;Tran F;Fredrich B;Fordter M;Franke A;Bojarski C;Glauben R;Löscher
• 通讯作者: Löscher

The role of adipose tissue in inflammatory bowel diseases

• DOI: 10.1097/mog.0000000000000445
• 发表时间: 2018-07
• 期刊: Current Opinion in Gastroenterology
• 影响因子: 2.5
• 作者: C. Weidinger;A. Hegazy;B. Siegmund