Disruption of tight junction structure contributes to secretory dysfunction in IgG4-related sialadenitis

Min, Sainan; Wu, Li‐Ling; Zhang, Yanyan; Zhu, Wenxuan; Cong, Xin; Yu, Guang‐Yan

doi:10.1007/s10735-019-09854-8

Cited by 10 publications

(13 citation statements)

References 49 publications

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“…The tissue processing was performed as described in our previous study. 43 Briefly, we homogenized the SMG tissues on ice and used 100 μg of homogenates per sample for proteomics screening. After lysis, the concentration of protein was quantified by the Bradford assay.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

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Section: Methodsmentioning

confidence: 99%

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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“…Knockout of claudin-1 in mice leads to loss of the TJ barrier to water and macromolecules at the stratum granulosum of the epidermis; consequently, these mice die of dehydration in the neonatal period [12]. Claudin-3 is decreased in the submandibular gland (SMG) and positively correlated with salivary function in patients with IgG4-related sialadenitis, a chronic fibroinflammatory disease characterized by salivary gland swelling and hyposalivation [13]. Differential expression patterns of claudins are detected in the salivary glands among species.…”

Section: Introductionmentioning

confidence: 99%

High Glucose Reduces the Paracellular Permeability of the Submandibular Gland Epithelium via the MiR-22-3p/Sp1/Claudin Pathway

Huang¹,

Liu²,

Mao³

et al. 2021

Cells

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Tight junctions (TJs) play an important role in water, ion, and solute transport through the paracellular pathway of epithelial cells; however, their role in diabetes-induced salivary gland dysfunction remains unknown. Here, we found that the TJ proteins claudin-1 and claudin-3 were significantly increased in the submandibular glands (SMGs) of db/db mice and high glucose (HG)-treated human SMGs. HG decreased paracellular permeability and increased claudin-1 and claudin-3 expression in SMG-C6 cells. Knockdown of claudin-1 or claudin-3 reversed the HG-induced decrease in paracellular permeability. MiR-22-3p was significantly downregulated in diabetic SMGs and HG-treated SMG-C6 cells. A miR-22-3p mimic suppressed claudin-1 and claudin-3 expression and abolished the HG-induced increases in claudin-1 and claudin-3 levels in SMG-C6 cells, whereas a miR-22-3p inhibitor produced the opposite effects. Specificity protein-1 (Sp1) was enhanced in diabetic SMGs and HG-treated SMG-C6 cells, which promoted claudin-1 and claudin-3 transcription through binding to the corresponding promoters. A luciferase reporter assay confirmed that miR-22-3p repressed Sp1 by directly targeting the Sp1 mRNA 3′-untranslated region (3′-UTR). Consistently, the miR-22-3p mimic suppressed, whereas the miR-22-3p inhibitor enhanced, the effects of HG on Sp1 expression. Taken together, our results demonstrate a new regulatory pathway through which HG decreases the paracellular permeability of SMG cells by inhibiting miR-22-3p/Sp1-mediated claudin-1 and claudin-3 expression.

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“…It has been shown that the secretory function of both organs is altered in IgG4-related disease (IgG4RD), a chronic inflammatory pathology. Reports have established a correlation between the expression levels of tight junction proteins and their specific localisation at the apical tight junction, and proper secretory function of pancreas and salivary gland 36 . Therefore, a role for MarvelD3 could be found in this particular pathological condition in these two glands.…”

Section: Discussionmentioning

confidence: 99%

Spatio-temporal expression pattern and role of the tight junction protein MarvelD3 in pancreas development and function

Heymans

Delcorte

Spourquet

et al. 2021

Sci Rep

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Tight junction complexes are involved in the establishment and maintenance of cell polarity and the regulation of signalling pathways, controlling biological processes such as cell differentiation and cell proliferation. MarvelD3 is a tight junction protein expressed in adult epithelial and endothelial cells. In Xenopus laevis, MarvelD3 morphants present differentiation defects of several ectodermal derivatives. In vitro experiments further revealed that MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behaviour and survival. In this work, we found that MarvelD3 is expressed from early developmental stages in the exocrine and endocrine compartments of the pancreas, as well as in endothelial cells of this organ. We thoroughly characterized MarvelD3 expression pattern in developing pancreas and evaluated its function by genetic ablation. Surprisingly, inactivation of MarvelD3 in mice did not alter development and differentiation of the pancreatic tissue. Moreover, tight junction formation and organization, cell polarization, and activity of the JNK-pathway were not impacted by the deletion of MarvelD3.

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Disruption of tight junction structure contributes to secretory dysfunction in IgG4-related sialadenitis

Cited by 10 publications

References 49 publications

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

High Glucose Reduces the Paracellular Permeability of the Submandibular Gland Epithelium via the MiR-22-3p/Sp1/Claudin Pathway

Spatio-temporal expression pattern and role of the tight junction protein MarvelD3 in pancreas development and function

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