Study of the ontogeny and development of resident intestinal macrophages both in the resting mucosa and during inflammation

• Applicant: Dr. Daniel Autenrieth
• Subject Area: Gastroenterology ; Immunology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242133256

As primary effector cells of the innate immune system macrophages play a vital role in the mucosal homeostasis of both small and large intestine, but are also involved in patho-mechanisms leading to inflammatory bowel disease. Both exact ontogeny and function of resident intestinal macrophages remain poorly understood. However, it is important to discriminate resident intestinal macrophages involved in homeostatic functions from the population of macrophages primarily seen during inflammatory processes in the intestinal mucosa. Due to their slow turnover in vivo, the ontogeny of resident intestinal macrophages has been difficult to determine. Conventionally, macrophages are considered to originate from hemapoietic stem cells (HSC) in the bone marrow. In a recent study by Schulz et al. published in Science macrophages in several non-intestinal tissues have been shown to be able to replenish independently from the bone marrow and to rather derive from yolk sac progenitors. Based on the identification this lineage of resident macrophages (F4/80bright) derived form HSC-independent progenitors in tissues such as skin, liver, spleen and pancreas, we raise the hypothesis that, similarly, HSC-independent progenitors might contribute to tissue macrophages in the intestinal lamina propria. Moreover, we hypothesize that the ontogenetic dichotomy of resident intestinal macrophages relevantly affects their function in the setting of inflammatory bowel disease.In the project proposal at hand, we describe a detailed research plan using several approaches. The transcription factor Myb is required for HSC development. In a first step we will examine the distribution of F4/80bright macrophages in the intestines of Myb-knockout mice. Furthermore we will use a fate mapping strategy to trace Yolk sac macrophages and their possible distribution in the murine intestines. In a complementary approach we plan to apply a transplantation model: After conditional deletion of the Myb gene, Myb positive BM-cells will be transplanted and the contribution of HSC-independent macrophages to the population of resident intestinal macrophages will be determined. In order to investigate the possible involvement of HSC-independent macrophages in inflammatory processes we will apply above fate mapping strategies in different chemical colitis models. With this research plan we expect to generate new findings towards the ontogeny of resident intestinal macrophages and their possible involvement in inflammatory processes in the intestine.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Frederic Geissmann, Ph.D.