Role of membrane-associated macrophages in health and inflammation

PROJECT SUMMARY/ ABSTRACT Mesenteritis is an inflammatory disorder of mesenteric tissues. It includes mesenteric lipodystrophy (mesenteric fat necrosis), mesenteric panniculitis (chronic mesenteric fibrosis) and mesenteric lymphadentis (mesenteric lymph node inflammation). It is diagnosed by an abdominal computed tomography (CT) scan; however, the cause of mesenteritis remains unknown. Emerging clinical evidence shows that mesenteritis is associated with gut inflammation such as IBD and Chron's Disease. As innate myeloid cells, macrophages are distributed throughout the whole organism and they play crucial roles in mediating tissue inflammation. Based on our supporting data, we identified macrophage populations in serous membrane of gut mesentery (termed membrane-associated macrophages). Thus, this research proposal seeks to address fundamental questions regarding the tissue specific role of membrane-associated macrophages in steady state and during mesenteritis induced gut inflammation. These include how membrane- associated macrophages are reprogrammed by local niches and gut inflammation. To better describe the role of these macrophages and its mechanism, we performed genetic studies of membrane-associated macrophages that provided insight into their roles in steady state and gut inflammation. These preliminary data results have led us to pursue to the following specific aims: (1) Determine distinct homeostatic functions of membrane-associated macrophages and local signals that shape their tissue specification; (2) Determine the role of membrane- associated macrophages during mesenteritis induced by gut inflammation. We will perform lineage tracing, cell ablation, transcriptomic analysis of membrane-associated macrophages and in vivo live imaging to understand the role and dynamic interactions of macrophages with local environment in steady state and during mesenteritis induced by gut inflammation. Ultimately, we hope our studies will lead to the discovery of therapeutic targets to prevent mesenteritis as well as gut inflammation.