Immunoproteasome Activation During Early Antiviral Response in Mouse Pancreatic β-cells: New Insights into Auto-antigen Generation in Type I Diabetes?

Freudenburg, Wieke; Gautam, Madhav; Chakraborty, Pradipta; James, Jared; Richards, Jennifer; Salvatori, Alison; Baldwin, Aaron C.; Schriewer, Jill; Buller, R. Mark; Corbett, John A.; Skowyra, Dorota

doi:10.4172/2155-9899.1000141

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…Ligand-free MHC molecules that reach the cell surface are rapidly degraded [10]. Thus, the presently observed long-lasting maintenance of MHC class I expression at the human beta cell surface may be due to the parallel abundance of antigenic peptides generated in response to IFNα [11]. …”

Section: Discussionmentioning

confidence: 99%

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

et al. 2018

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Aim/hypothesis IFNα, a cytokine expressed in human islets from type 1 diabetes patients, plays a key role in the pathogenesis of diabetes by up-regulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We presently tested whether expression of these mediators of beta cell loss is reversible upon IFNα withdrawal or IFNα pathway inhibition. Methods IFNα-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and RT-PCR in human EndoC-βH1 cells or human islets exposed to IFNα with or without the presence of JAK inhibitors. Protein expression was evaluated by western blot. Results IFNα-induced expression of inflammatory and ER stress markers returned to baseline after 24–48 h following cytokine removal. By contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, added together with IFNα, prevented MHC class I overexpression, but when added 24 h after IFNα exposure these inhibitors failed to accelerate MHC class I return to baseline. Conclusion/interpretation IFNα mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFNα-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phases of type 1 diabetes and that IFNα-inhibitors might need to be used at very early stages of the disease to be effective.

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Section: Discussionmentioning

confidence: 99%

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

et al. 2018

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“…While non-immune cells express standard proteasomes almost exclusively, immunoproteasome expression can be induced in such cells following exposure to IFN-γ. As mentioned above, type I IFNs can also upregulate the immunoproteasome, although less efficiently than IFN-γ ( Shin et al, 2006 ; Freudenburg et al, 2013a , b ). An initial report suggested that TNF-α could act synergistically with IFN-γ to upregulate β5i expression ( Hallermalm et al, 2001 ), implying that other proinflammatory cytokines may be capable of regulating immunoproteasome expression.…”

Section: Immunoproteasome Formation and Tissue Expressionmentioning

confidence: 96%

“…Expression of the three immunosubunits following IFN-γ stimulation is mediated by interferon (IFN) regulatory factor-1 (IRF-1; Chatterjee-Kishore et al, 1998 ; Foss and Prydz, 1999 ; Brucet et al, 2004 ; Namiki et al, 2005 ). Type I IFNs can also upregulate the immunoproteasome, although higher concentrations are needed to achieve the same upregulation induced by IFN-γ ( Shin et al, 2006 ; Freudenburg et al, 2013a , b ).…”

Section: Standard Proteasomes and Immunoproteasomesmentioning

confidence: 99%

The immunoproteasome and viral infection: a complex regulator of inflammation

2015

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During viral infection, proper regulation of immune responses is necessary to ensure successful viral clearance with minimal host tissue damage. Proteasomes play a crucial role in the generation of antigenic peptides for presentation on MHC class I molecules, and thus activation of CD8 T cells, as well as activation of the NF-κB pathway. A specialized type of proteasome called the immunoproteasome is constitutively expressed in hematopoietic cells and induced in non-immune cells during viral infection by interferon signaling. The immunoproteasome regulates CD8 T cell responses to many viral epitopes during infection. Accumulating evidence suggests that the immunoproteasome may also contribute to regulation of proinflammatory cytokine production, activation of the NF-κB pathway, and management of oxidative stress. Many viruses have mechanisms of interfering with immunoproteasome function, including prevention of transcriptional upregulation of immunoproteasome components as well as direct interaction of viral proteins with immunoproteasome subunits. A better understanding of the role of the immunoproteasome in different cell types, tissues, and hosts has the potential to improve vaccine design and facilitate the development of effective treatment strategies for viral infections.

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“…6). IRF1, a transcription factor involved in type I IFN-stimulated gene expression, contributes to IFN-stimulated expression of the immunoproteasome, which promotes antigen processing for presentation by MHC class I molecules (30). As observed in Supplementary Fig.…”

Section: Tyk2 Kd Prevents Pic-and Ifna-induced Mhc Class I Protein Exmentioning

confidence: 84%

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

et al. 2015

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Pancreatic b-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic b-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human b-cells exposed to polyinosinicpolycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNa and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early b-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PICinduced b-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic b-cells via modulation of IFNa signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.

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Immunoproteasome Activation During Early Antiviral Response in Mouse Pancreatic β-cells: New Insights into Auto-antigen Generation in Type I Diabetes?

Cited by 13 publications

References 34 publications

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

The immunoproteasome and viral infection: a complex regulator of inflammation

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

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