CX₃CR1 deficiency exacerbates neuronal loss and impairs early regenerative responses in the target-ablated olfactory epithelium

Mol Cell Neurosci. 2011 Nov;48(3):236-45. doi: 10.1016/j.mcn.2011.08.004. Epub 2011 Aug 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Death / genetics
  • Cytokines / genetics
  • Cytokines / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Regeneration / physiology*
  • Neurogenesis / genetics*
  • Olfactory Bulb / cytology
  • Olfactory Bulb / metabolism
  • Olfactory Bulb / surgery
  • Olfactory Mucosa / cytology
  • Olfactory Mucosa / metabolism*
  • Olfactory Receptor Neurons / cytology
  • Olfactory Receptor Neurons / metabolism*
  • Receptors, Chemokine / genetics*
  • Receptors, Chemokine / metabolism


  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Cytokines
  • Receptors, Chemokine