title: CX₃CR1 deficiency exacerbates neuronal loss and impairs early regenerative responses in the target-ablated olfactory epithelium.
abstract: The olfactory epithelium is a site of sustained adult neurogenesis where olfactory sensory neurons are continuously replaced from endogenous stem/progenitor cells. Epithelial macrophages have been implicated in the phagocytosis of degenerating cells but the molecular mechanisms allowing for their recruitment and activation while maintaining a neurogenic microenvironment are poorly understood. We have previously shown that the chemokine fractalkine (CX₃CL1) is expressed by olfactory sensory neurons and ensheathing cells in the olfactory epithelium. In turn, the fractalkine receptor, CX₃CR1, is expressed on macrophages and dendritic cells within the olfactory epithelium. We report that a selective cell death of olfactory sensory neurons in the epithelium of CX₃CR1-deficient mice via target ablation (i.e. olfactory bulbectomy) results in an exacerbated loss of olfactory sensory neurons compared to wild-type mice. In addition, reduced proliferation of intraepithelial stem/progenitor cells was observed in lesioned CX₃CR1-deficient mice, suggesting an impaired regenerative response. Importantly, a lack of CX₃CL1-signaling caused increased recruitment of macrophages into the olfactory epithelium, which in turn contained higher levels of pro-inflammatory cytokines (e.g. TNF-α and IL-6) as determined by qPCR. We also present novel data showing that, relative to wild-type, CX₃CR1-deficient macrophages have diminished phagocytic activity following stimulation with CX₃CL1. Collectively, our data indicate that signaling through the CX₃CR1 receptor modulates macrophage activity, resulting in an environment conducive to olfactory sensory neuron clearance and targeted replacement from endogenous stem/progenitor cells.
authors.affiliation: School of Anatomy and Human Biology, The University of Western Australia, Perth, Australia.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Blomster
authors.forename: Jana
authors.initials: J
authors.lastname: Vukovic
authors.forename: Debbie A E
authors.initials: DA
authors.lastname: Hendrickx
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Alan R
authors.initials: AR
authors.lastname: Harvey
authors.forename: Luis
authors.initials: L
authors.lastname: Filgueira
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Ruitenberg
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D016923:Cell Death / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics*; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D009831:Olfactory Mucosa / Q000166:cytology / Q000378:metabolism*; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D019707:Receptors, Chemokine