Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients
Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflamm...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00506/full |
| _version_ | 1818536353370996736 |
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| author | Eirini Apostolou Eirini Apostolou Petros Moustardas Petros Moustardas Takao Iwawaki Athanasios G. Tzioufas Athanasios G. Tzioufas Giannis Spyrou |
| author_facet | Eirini Apostolou Eirini Apostolou Petros Moustardas Petros Moustardas Takao Iwawaki Athanasios G. Tzioufas Athanasios G. Tzioufas Giannis Spyrou |
| author_sort | Eirini Apostolou |
| collection | DOAJ |
| description | Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity.Methods:In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate).Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice.Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS. |
| first_indexed | 2024-12-11T18:36:51Z |
| format | Article |
| id | doaj.art-1f14600411c1414a884ca3e7ceff19ca |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T18:36:51Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1f14600411c1414a884ca3e7ceff19ca2022-12-22T00:54:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00506437611Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human PatientsEirini Apostolou0Eirini Apostolou1Petros Moustardas2Petros Moustardas3Takao Iwawaki4Athanasios G. Tzioufas5Athanasios G. Tzioufas6Giannis Spyrou7Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceAcademic Joint Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceDivision of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceDivision of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, JapanDepartment of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceAcademic Joint Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, GreeceDivision of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenObjective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity.Methods:In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate).Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice.Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.https://www.frontiersin.org/article/10.3389/fimmu.2019.00506/fullERdj5ER-stressautoimmunitysalivary glandSjögren's syndromeXBP1 |
| spellingShingle | Eirini Apostolou Eirini Apostolou Petros Moustardas Petros Moustardas Takao Iwawaki Athanasios G. Tzioufas Athanasios G. Tzioufas Giannis Spyrou Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients Frontiers in Immunology ERdj5 ER-stress autoimmunity salivary gland Sjögren's syndrome XBP1 |
| title | Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients |
| title_full | Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients |
| title_fullStr | Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients |
| title_full_unstemmed | Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients |
| title_short | Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients |
| title_sort | ablation of the chaperone protein erdj5 results in a sjogren s syndrome like phenotype in mice consistent with an upregulated unfolded protein response in human patients |
| topic | ERdj5 ER-stress autoimmunity salivary gland Sjögren's syndrome XBP1 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00506/full |
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