Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model

• Type of Material: Article
• Authors: Sairam V Jabba, Kansas State University; Alisha Oelke, Kansas State University; Ruchira Singh, Kansas State University; Rajanikanth J Maganti, Kansas State University; Sherry Fleming, Kansas State University; Susan M Wall, Emory University; Lorraine A Everett, National Institutes of Health; Eric D Green, National Institutes of Health; Philine Wangemann, Kansas State University
• Language: English
• Date: 2006
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2006 Jabba et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.biomedcentral.com/1741-7015/4/37
• Title of Journal or Parent Work: BMC Medicine
• ISSN: 1741-7015
• Volume: 4
• Issue: 37
• Grant/Funding Information: Breeding of the mice at KSU and the work reported in this paper was supported by grant NIH-R01-DC01098 to PW from the National Institutes on Deafness and Other Communication Disorders, National Institutes of Health.; Breeding and shipping of Slc26a4+/+ and Slc26a4-/- mice from Emory University was funded by grant NIH-R01-DK52935 to SW.; The creation of the mice was supported in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health.; The Confocal Core and the Molecular Biology Core at KSU were funded by NIH-P20-RR017686 from the National Institute for Research Resources, National Institutes of Health.
• Research Categories: Health Sciences, General; Biology, Molecular

Abstract

Background Pendred syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Methods Slc26a4-/- and age-matched control (Slc26a4+/+ or Slc26a4+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Results Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68, a marker for macrophages. Marginal cells in Slc26a4-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs, C3 and Cd45 was found in stria vascularis of P15 Slc26a4+/- and Slc26a4-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a, Il6, Il12a, Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45), Cd68, Cd83, Lyzs, Lgals3 (= Mac2 antigen), Msr2, Cathepsins B, S, and K (Ctsb, Ctss, Ctsk) and complement components C1r, C3 and C4 was significantly increased in stria vascularis of adult Slc26a4-/- mice compared to Slc26a4+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4-/- compared to Slc26a4+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen. Conclusion The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred syndrome.