Thèse de doctorat
Résumé : Chemerin, a chemoattractant factor (and potentially an adipokine), is the product of tazarotene-induced gene 2 (TIG2) or retinoid acid receptor responder 2 (RARRES2). It is found to be the endogenous ligand for chemokine-like receptor 1 (CMKLR1), aka ChemR23 or Chemerin1. By modulating the transport of certain leukocyte populations (i.e., macrophages, dendritic cells, and natural killer cells), chemerin seems to be involved in the regulation of inflammatory conditions in different disease models and depicts pro- or anti-inflammatory characteristics depending on the study model. In addition, as an adipokine, chemerin has been shown to be involved in a repertoire of metabolic syndromes such as type 2 diabetes mellitus and cardiovascular diseases but its exact function in this context is not yet understood. Therefore, the multifunctional nature of chemerin in vivo remains an open question. Zebrafish became over recent years a major animal model in many research fields, including inflammation, leukocyte biology, and cancer. We decided to exploit the unique strengths of this model to complement the ongoing studies in mice and obtain new insights into key functional aspects of chemerin. Sequence and phylogenetic investigations suggested that due to several duplication events (including the teleost-specific whole genome duplication event), there are more chemerin and receptor genes in zebrafish compared to mammals. Our thorough analysis of the chemerin system in the zebrafish indicated that the different chemerin paralogs exhibit distinct pharmacological and expression properties. We further validated these results using knockout lines generated by us or available in the lab. These observations strongly suggest that subfunctionalization contributed to the evolution of the chemerin family in zebrafish, which may provide an advantage for the in vivo functional dissection of chemerin activities in physiology and disease. In addition, we also demonstrated that, as in human and mouse, accurate and specific C-terminal processing of chemerin is required for bioactivity in zebrafish. Consequently, it seems that the chemerin system is indeed conserved in zebrafish, thus, this model can be used to complement the ongoing studies in mammals and further address the questions concerning the pleiotropic nature of chemerin.