Role of chemerin and its receptor ChemR23 in the physiopathology of inflammatory lung diseases ; Caractérisation du rôle de la chémérine et de son récepteur ChemR23 dans la physiopathologie des maladies pulmonaires inflammatoires

Chemoattractant agents play a crucial role in the initiation of immune responses, by regulating the traffic and function of leucocyte populations. Their receptors are therefore considered as potential targets for the development of new therapies in the fields of cancer and inflammatory diseases. ChemR23, a previously orphan receptor discovered in the laboratory, is structurally related to receptors for chemoattractant agents. It is expressed on immature myeloid and plasmacytoid dendritic cells (mDCs and pDCs respectively), as well as on adipocytes, macrophages, NK and endothelial cells. Chemerin, the endogenous ligand of ChemR23, is abundant in various human samples originating from inflammatory diseases, including pleural effusions. Chemerin is secreted as an inactive precursor, prochemerin, and is activated by the removal of six or seven amino-acids from its carboxy-terminus by serine proteases, such as as cathepsin G and elastase. Chemerin acts as a chemoattractant agent of low nanomolar potency for macrophages, immature mDCs and pDCs. It is however more active on pDCs, in line with the higher expression of ChemR23 on these cells. pDCs possess important immunoregulatory properties in lung diseases, and their ability to secrete large amounts of type I interferon (IFN) upon viral infection makes them crucial players in anti-viral immunity. According to these elements, and to the role of neutrophils in the physiopathology of many inflammatory lung diseases and in the generation of active chemerin, we began in 2007 to study the role of chemerin and its receptor ChemR23 in inflammatory lung diseases. We first characterized the mouse chemerin/ChemR23 system, and described that this system was very similar to the human one, in terms of distribution, pharmacology and functional properties. We then used wild type mice (WT) and mice invalidated for the receptor (ChemR23-/-) in various models of inflammatory lung diseases, including asthma, lung fibrosis, viral pneumonia, and acute lung injury. Whereas the asthma and ...