Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model.
Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model.
复制标题
DOI：
10.1186/1741-7015-4-37
复制
发表时间：
2006-12-22
期刊：
影响因子：
9.3
通讯作者：
Wangemann P
中科院分区：
文献类型：
--
作者：
Jabba SV;Oelke A;Singh R;Maganti RJ;Fleming S;Wall SM;Everett LA;Green ED;Wangemann P
Pendred综合征是一种常染色体隐性遗传疾病，以耳聋和甲状腺肿大为特征，由编码阴离子交换蛋白pendrin的SLC 26 A4突变引起。我们使用具有（Slc 26 a4 +/+或Slc 26 a4 +/-）或缺乏（Slc 26 a4-/-）完整Slc 26 a4基因的小鼠研究pendrin表达与耳聋之间的关系。以前，我们报告说，成年Slc 26 a4-/-小鼠的血管纹色素沉着，边缘细胞出现紊乱。在这里，我们确定色素沉着过度和边缘细胞解体的时间进程，并测试炎症导致这种组织变性的假设。在四个出生后（P）发育阶段研究了Slc 26 a4-/-和年龄匹配的对照（Slc 26 a4 +/+或Slc 26 a4 +/-）小鼠：标志听力开始的年龄之前和之后（分别为P10和P15），断奶后（P28-41）和成年后（P74-170）。共聚焦显微镜观察血管纹变性和色素沉着。采用基因芯片和定量RT-PCR技术分析血管纹基因表达。此外，在螺旋韧带、脾脏和肝脏中定量选择的一组基因的表达，以评价在血管纹中观察到的表达变化是否对血管纹或系统性具有特异性。在P10或P15时未观察到血管纹变性（定义为色素沉着过度和边缘细胞解体），但发生在断奶后，并与巨噬细胞标记物CD 68染色相关。然而，Slc 26 a4-/-中的边缘细胞在P10和P15时具有更大的顶端表面积。在P15 Slc 26 a4 +/-和Slc 26 a4-/-小鼠血管纹中未发现Lyzs、C3和Cd 45的表达差异。然而，在断奶后和成年小鼠中发现表达差异。在P15、断奶后和成年时，急性炎症标志物Il 1a、Il 6、Il 12 a、Nos 2和Nos 3的表达没有差异。与Slc 26 a4 +/+小鼠相比，成年Slc 26 a4-/-小鼠血管纹中巨噬细胞标志物包括Ptprc（= Cd 45）、Cd 68、Cd 83、Lyzs、Lgals 3（= Mac 2抗原）、Msr 2、组织蛋白酶B、S和K（Cts B、Ctss、Ctsk）以及补体组分C1 r、C3和C4的表达显著增加。与Slc 26 a4 +/-小鼠相比，Slc 26 a4-/-小鼠血管纹中巨噬细胞标志物Cd 45和Cd 84以及补体成分C1 r和C3的表达增加，但螺旋韧带、肝脏或脾脏中的表达没有增加。Lyzs在血管纹和螺旋韧带中的表达增加，而在肝脏和脾脏中的表达不明显。数据表明，在Slc 26 a4-/-小鼠中血管纹的色素沉着过度和边缘细胞重组发生在断奶后，与巨噬细胞的侵入一致。这些数据表明，巨噬细胞的侵入有助于血管纹中的组织变性，并且巨噬细胞的侵入仅限于血管纹，而不是系统性的。血管纹变性的延迟发作表明，存在恢复/保留小鼠听力的机会之窗，因此可能在患有Pendred综合征的人类中也存在。
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. 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. 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. 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.
登录
查看更多内容
影响因子：
16.2
作者：
Vetter, DE;Mann, JR;Barhanin, J
通讯作者：
Barhanin, J
影响因子：
4.8
作者：
Royaux, IE;Suzuki, K;Green, ED
通讯作者：
Green, ED
影响因子：
5.8
作者：
Bidart, JM;Mian, C;Schlumberger, M
通讯作者：
Schlumberger, M
DOI：
10.1007/s10162-002-3052-4
发表时间：
2003-09-01
影响因子：
2.4
作者：
Royaux, IE;Belyantseva, IA;Green, ED
通讯作者：
Green, ED
影响因子：
30.8
作者：
Scott, DA;Wang, R;Karniski, LP
通讯作者：
Karniski, LP