High Endothelial Venules (HEV) and Chronic Inflammatory Diseases – HEV-CID

THE CURRENT PROPOSAL IS A BASIC RESEARCH PROJECT (For confidentiality reasons, the strategies, tools and specific tasks of the project will not be described in this public abstract; for reviewing purpose, please see the 3 confidential abstracts). Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel diseases, atherosclerosis, asthma, ….) represent frequent, serious and often life-threatening conditions that have a major impact on the quality of life and life expectancy. A better understanding of the cellular and molecular mechanisms involved in chronic inflammation is thus urgently needed, because it may provide the basis of novel therapeutic approaches for chronic inflammatory diseases. The current proposal aims at the characterization of high endothelial venules (HEV), specialized blood vessels that support high levels of lymphocyte recruitment from the blood. HEV blood vessels are found in lymphoid organs and chronically inflamed tissues in many diseases (rheumatoid arthritis, inflammatory bowel diseases, atherosclerosis, bronchial asthma, autoimmune thryroiditis, Helicobacter pylori gastritis, chronic vascular rejection of kidney and heart grafts,...). Such vessels have been proposed to participate in a positive feedback mechanism for increasing lymphocyte entry into the diseased tissue, thus contributing to the amplification and maintenance of chronic inflammation. Interfering with the development and/or maintenance of HEV blood vessels in chronically inflamed tissues is therefore likely to provide therapeutic benefits in many distinct human chronic inflammatory diseases. However, very little is known yet about the molecular mechanisms regulating formation of HEV blood vessels. We recently discovered that CD11c+ dendritic cells (DCs) play a critical role in the maintenance of HEV characteristics in adult mouse lymph nodes (Moussion and Girard, Nature 2011, 479:542-546). Our results indicated that DC-derived lymphotoxin LTa1b2 and LTbR receptor expressed on HEV endothelial cells, are involved in the cross-talk between DCs and HEV. The major objective of the current project is to increase the current knowledge about HEV blood vessels by providing answers to several important questions: What are the signalling pathways, transcription factors and possibly regulatory non-coding RNAs characteristics of the HEV endothelial cell phenotype in vivo ? What are the mechanisms involved in the induction and maintenance of HEV blood vessels in chronically inflamed tissues and lymphoid organs ? The major aims of the project will be addressed through the use of multi-disciplinary approaches and tools: molecular and cellular biology, in vivo cell depletion and generation of mixed bone marrow chimeras using transgenic mouse lines, next-generation sequencing, bioinformatics, immunohistology and intravital microscopy imaging. All the tasks will be performed by the team of Dr Jean-Philippe GIRARD (DR1 INSERM, Director of IPBS-CNRS-Université de Toulouse), a vascular biologist and molecular/cellular biologist who has a long standing expertise on HEV blood vessels (Immunity 1995, PNAS 1999, Blood 2004, Nature 2011): Team “Vascular biology: Endothelial Cells, Inflammation and Cancer” (IPBS-CNRS-Université de Toulouse; A+ AERES), a multidisciplinary team which regroups researchers, engineers, technicians and PhD students with complementary expertise in vascular biology, molecular and cellular biology, immunology, physiology and in vivo imaging.