G protein-coupled receptors (GPCR) represent the largest family among membrane receptors. They play a major role in a variety of physiological and pathophysiological processes and constitute the targets for 30% of the active compounds presently used as therapeutic agents. Our objective is to study new paradigms in activation, signalling and regulation of GPCRs and determine their contribution in pathophysiological processes using mice models.
The experimental approach involves cell and molecular biology, pharmacology, organoid culture technology and in vivo studies.
Supervisor: Dr. Jean Yves Springael
The main objective of this project is to investigate the impact of the chemerin/CMKLR1 signaling axis on microglial cells (MG) function within the retina. Chemerin, a small chemotactic cytokine, exerts its biological effects by activating the G protein-coupled receptor CMKLR1/CHEMR231. Within the retina, chemerin is primarily expressed by Müller cells and retinal pigment epithelial cells (RPE), while CMKLR1 is expressed by MG. In a healthy retina, MG integrate regulatory signals from neighboring cells, including Müller cells, to maintain retinal homeostasis and support immune surveillance2,3. However, with aging or under pathological conditions such as age-related macular degeneration, retinitis pigmentosa or diabetic retinopathy, MG become activated and migrate from the inner retina layers to damaged areas such as the sub-retinal space, where they physically interact with RPE2,4.
The precise mechanisms by which MG integrate chemerin signals from Müller cells and RPE, and transition from a homeostatic state to one that promotes disease progression, remain unclear. The primary objectives of this project are to (i) determine the impact of chemerin on the transcriptomic profile of retinal MG, and (ii) investigate whether the chemerin/CMKLR1 axis plays a role in MG function under homeostatic and pathological conditions by using transgenic mice lacking CMKLR1 expression in MG.
The project has received financial support from the Belgian National Fund for Scientific Research (FNRS), and we are looking for a dynamic and motivated student to lead this new project.
- Bondue, B. et al. Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism. Cytokine Growth Factor Rev. 22, 331–338 (2011).
- Fan, W. et al. Retinal microglia: Functions and diseases. Immunology 166, 268–286 (2022).
- Hu, X. et al. Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma. J. Neuroinflammation 18, 303 (2021).
- Jo, D. H. et al. Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy. Glia 67, 321–331 (2019).