Innate immune response in adipocytes: impact for intestinal inflammation

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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.