Disruption of tight junction structure contributes to secretory dysfunction in IgG4-related sialadenitis
Disruption of tight junction structure contributes to secretory dysfunction in IgG4-related sialadenitis
复制标题
紧密连接结构的破坏导致 IgG4 相关唾液腺炎的分泌功能障碍
DOI：
10.1007/s10735-019-09854-8
复制
发表时间：
2020-02-01
影响因子：
3.2
通讯作者：
Yu, Guang-Yan
中科院分区：
文献类型：
--
作者：
Min, Sai-Nan;Wu, Li-Ling;Yu, Guang-Yan
IgG 4相关性涎腺炎（IgG 4-RS）是一种慢性纤维炎性疾病，其特征是唾液腺肿胀和不同程度的口干。紧密连接（TJs）通过调节离子和水的细胞旁流动在维持分泌功能中起重要作用。然而，TJ是否改变并导致IgG 4-RS分泌不足还不完全清楚。在此，共鉴定了399个在IgG 4-RS下颌下腺（SMG）中差异表达的蛋白，并且富集在肌动蛋白细胞骨架和唾液分泌的调节中。Real-time PCR结果显示，在IgG 4-RS SMG中，claudin-3、-4、-6、-7、-8、-10、-12、occludin和ZO-1的mRNA水平显著降低，而claudin-1和-5的mRNA水平升高。免疫组织化学和免疫荧光染色显示，对照组SMG的腺泡和导管中claudin-1、claudin-3、claudin-4、occludin和ZO-1主要分布于顶外侧膜，而IgG 4-RS SMG的顶外侧膜中claudin-1蛋白表达增强，claudin-3、claudin-4和ZO-1蛋白表达减弱。在SMG中，Occludin弥散分布于腺泡和导管的胞浆中。其中，claudin-3和ZO-1蛋白水平与唾液流率呈正相关。此外，在IgG 4-RS SMG的腺泡和导管细胞中观察到顶侧膜周围的F-actin荧光强度降低和相同位置的ZO-1染色丢失，这可能是导致TJ复合体结构紊乱的原因。总之，这些结果表明SMG的TJ复合物的完整性受损，可能导致IgG 4-RS患者的唾液分泌减少。
IgG4-related sialadenitis (IgG4-RS) is a chronic fibro-inflammatory disease characterized by swelling of salivary glands and varying degrees of xerostomia. Tight junctions (TJs) play an essential role in maintaining secretory function by regulating the paracellular flow of ions and water. However, whether TJs are altered and contribute to the hyposecretion in IgG4-RS is not fully understood. Here, a total of 399 differentially expressed proteins were identified in IgG4-RS submandibular glands (SMGs) and enriched in the regulation of actin cytoskeleton and the salivary secretion. Real-time PCR results showed that the mRNA levels of claudin-3, -4, -6, -7, -8, -10, -12, occludin, and ZO-1 were significantly lower, whereas claudin-1 and -5 were higher in IgG4-RS SMGs. Immunohistochemical and immunofluorescence staining revealed that claudin-1, -3, -4, occludin, and ZO-1 were mainly distributed at apicolateral membranes in acini and ducts of SMGs from controls, whereas claudin-1 protein intensity at apicolateral membrane was elevated, while the staining of claudin-3, -4, and ZO-1 were reduced in IgG4-RS SMGs. Occludin was dispersed into cytoplasm of acini and ducts in SMGs of patients. Among them, claudin-3 and ZO-1 protein levels were positively correlated with saliva flow rate. Furthermore, the decreased fluorescence intensity of F-actin at peri-apicolateral membranes and the loss of ZO-1 staining at the same location were observed in acinar and ductal cells of IgG4-RS SMGs, which might be responsible for disorganization of TJ complex. Taken together, these findings indicate that the integrity of TJ complex of SMGs is impaired and might contribute to hyposalivation of IgG4-RS patients.