Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury
We recently demonstrated that selective hair cell ablation without any accompanying cochlear pathology in huDTR‐Pou4f3DTR/+ mice (Golub et al., 2012; Tong et al., 2015) is sufficient to recruit leukocytes into the cochlea and results in sustained elevation of macrophage numbers in the spiral ganglion (SG). Our data further suggest that SGNs communicate with macrophages via the ligand fractalkine (CX3CL1), that is expressed on expressed by SGNs, interacting with its receptor, CX3CR1, that is expressed by cochlear macrophages. We also found that disruption of fractalkine signaling after hair cell death results in decreased macrophage recruitment into the injured cochlea as well as enhanced loss of SGNs (Kaur et al., 2015). Together, our findings have revealed a critical role for macrophages in auditory pathology and suggest that macrophages have a neuroprotective role via fractalkine signaling in the injured cochlea.
Fractalkine is a chemokine that is expressed as a membrane bound glycoprotein on neurons (Harrison et al., 1998), peripheral endothelial cells (Bazan et al., 1997; Harrison et al., 2001; Rossi et al., 1998), and epithelial cells (Lucas et al., 2001). The fractalkine receptor (CX3CR1) is present on microglia and circulating monocytes, dendritic cells, and natural killer cells (Cook et al., 2001; Jung et al., 2000) and also expressed on cochlear macrophages (Hirose, Discolo, Keasler, & Ransohoff, 2005). Fractalkine occurs in two different forms: as a membrane‐bound protein tethered to neuronal membranes by a mucin‐like stalk, and as a soluble factor released upon cleavage of its N‐terminal chemokine domain (Garton et al., 2001). The extracellular chemokine domain of fractalkine is proteolytically cleaved from the membrane‐bound fraction by the lysosomal cysteine protease, cathepsin S and members of a disintegrin and metalloproteinase (ADAM) family such as ADAM‐10 and ADAM‐17. The soluble chemokine domain of fractalkine, when cleaved, can act as chemoattractant promoting cellular migration, whereas, membrane‐tethered mucin‐stalk of fractalkine has been proposed to act as an adhesion molecule for leukocytes during inflammation (Haskell, Cleary, & Charo, 1999; Hermand et al., 2008). In the central nervous system, fractalkine signaling has been suggested to control microglial neurotoxicity during certain neurodegenerative and neuroinflammatory conditions (Cardona et al., 2006). In humans, two single‐nucleotide polymorphisms (SNPs) produce four allelic receptor variants (Faure et al.