Role of chemokine receptors in the olfactory system

The olfactory epithelium provides the unique ability to regenerate odor detecting sensory neurons throughout life by a process called neurogenesis. The replacement of olfactory sensory neurons occurs upon regular cell death or lesion of the epithelium. The membrane receptor CXC chemokine receptor 4 (CXCR4), expressed in the neuronal lineage, regulates neurogenesis under control of its ligand CXC motif chemokine 12 (CXCL12). As shown for other tissues, such as the developing brain, the concentration of extracellular CXCL12 is tightly controlled by the atypical chemokine receptor 3 (ACKR3), which binds and internalizes CXCL12, thereby reducing its extracellular abundance. Thus, CXCR4 and ACKR3 are often co-expressed in the same tissue, where ACKR3 induces a CXCL12 gradient to ensure proper signaling and migration of CXCR4-expressing cells. This thesis aims to characterize the role of ACKR3 within the olfactory epithelium and to evaluate chemokine receptor mediated neurogenesis as a generic concept in the olfactory system. Experimental approaches included transgenic mouse models, immunofluorescence, qPCR, RNA sequencing and analysis of single-cell RNA-seq data. ACKR3 expressed by olfactory glia cells was found to adjust extracellular CXCL12 abundance and regulate CXCR4-mediated neurogenesis. In addition, the glia cell specific knockout of Ackr3 triggered an immune response of the olfactory epithelium with increased immune cell invasion and upregulation of immune defense genes. Finally, the neuronal lineage specific knockout of Cxcr4 in the vomeronasal organ demonstrated altered tissue composition, confirming a CXCR4-mediated effect on neurogenesis and on abundance of non-neuronal cell types, thereby supporting the concept of chemokine receptor mediated neurogenesis as a generic principle within the olfactory system. In conclusion, this thesis highlights chemokine receptor mediated neurogenesis and regulation of local immune responses within the olfactory system.