Expression of Fractalkine Receptor CX3CR1 on Cochlear Macrophages Influences Survival of Hair Cells Following Ototoxic Injury

Sato, Eisuke; Shick, H. Elizabeth; Ransohoff, Richard M.; Hirose, Keiko

doi:10.1007/s10162-009-0198-3

Cited by 92 publications

(126 citation statements)

References 38 publications

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“…Prior studies have demonstrated that macrophages are recruited into the cochlea after acoustic trauma (Fredelius and RaskAndersen, 1990;Hirose et al, 2005) or aminoglycoside ototoxicity (Sato et al, 2010). However, it is unclear whether this increase in macrophages was entirely attributable to hair cell death or whether other tissue injury caused by noise or ototoxic insults might also attract macrophages.…”

Section: Dt-induced Hair Cell Ablation Recruits Macrophages To the Damentioning

confidence: 99%

“…Macrophages are recruited into the cochlea after acoustic trauma (Fredelius and Rask-Andersen, 1990;Hirose et al, 2005) and aminoglycoside ototoxicity (Sato et al, 2010). However, because both noise and ototoxins can injure multiple cell types within the ear, it was unclear whether the injury-evoked increase in macrophages was caused by hair cell death or by damage to nonsensory tissues of the cochlea.…”

Section: Loss Of Cochlear Hair Cells Is Sufficient For Macrophage Recmentioning

confidence: 99%

“…The mammalian cochlea contains a population of resident macrophages, and increased numbers of macrophages are recruited into the cochlea after acoustic trauma or ototoxic injury (Fredelius and RaskAndersen, 1990;Hirose et al, 2005;Sato et al, 2010). Still, the precise role of macrophages in the lesioned cochlea is not known and the signals that recruit macrophages into injured ear have not been identified.…”

Section: Introductionmentioning

confidence: 99%

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Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

et al. 2015

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Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells. We used a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX 3 CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea.

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Section: Dt-induced Hair Cell Ablation Recruits Macrophages To the Damentioning

confidence: 99%

Section: Loss Of Cochlear Hair Cells Is Sufficient For Macrophage Recmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

et al. 2015

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“…These effector molecules activated by inflammation are relatively understudied elements of inner ear dysfunction. Mononuclear phagocyte migration into the inner ear, which has been observed in inner ear injury, could play an important role in hearing and balance dysfunction and is accompanied by other inflammatory mediators that affect the short and long term function of the inner ear in the disease state (Hirose et al 2005;Sato et al 2010). In many organ systems, inflammation is accompanied by changes in vascular permeability, and LPS is only one of many ways to stimulate local or systemic inflammation.…”

Section: Systemic Inflammation Induced By Lps Causes Compromise Of Thmentioning

confidence: 99%

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Hirose

Hartsock

Johnson

et al. 2014

JARO

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The blood vessels that supply the inner ear form a barrier between the blood and the inner ear fluids to control the exchange of solutes, protein, and water. This barrier, called the blood-labyrinth barrier (BLB) is analogous to the blood-brain barrier (BBB), which plays a critical role in limiting the entry of inflammatory and infectious agents into the central nervous system. We have developed an in vivo method to assess the functional integrity of the BLB by injecting sodium fluorescein into the systemic circulation of mice and measuring the amount of fluorescein that enters perilymph in live animals. In these experiments, perilymph was collected from control and experimental mice in sequential samples taken from the posterior semicircular canal approximately 30 min after systemic fluorescein administration. Perilymph fluorescein concentrations in control mice were compared with perilymph fluorescein concentrations after lipopolysaccharide (LPS) treatment (1 mg/kg IP daily for 2 days). The concentration of perilymphatic fluorescein, normalized to serum fluorescein, was significantly higher in LPS-treated mice compared to controls. In order to assess the contributions of perilymph and endolymph in our inner ear fluid samples, sodium ion concentration of the inner ear fluid was measured using ion-selective electrodes. The sampled fluid from the posterior semicircular canal demonstrated an average sodium concentration of 145 mM, consistent with perilymph. These experiments establish a novel technique to assess the functional integrity of the BLB using quantitative methods and to provide a comparison of the BLB to the BBB.

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“…CX3CR1 GFP/GFP male mice were acquired from The Jackson Laboratory and bred with C57Bl/6 females to produce CX3CR1 GFP/+ mice. These heterozygous mice have been used in previous studies of inner ear macrophages, which indicated that CX3CR1 GFP/+ mice have normal macrophage function in the inner ear and express GFP exclusively in macrophages (Hirose et al 2005;Sautter et al 2006;Sato et al 2008Sato et al , 2010.…”

Section: Cx3cr1 Gfp/+ Micementioning

confidence: 99%

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Expression of Fractalkine Receptor CX3CR1 on Cochlear Macrophages Influences Survival of Hair Cells Following Ototoxic Injury

Cited by 92 publications

References 38 publications

Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

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