Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity
BackgroundType 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune res...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1504583/full |
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| author | Matthew C. Austin Charanya Muralidharan Saptarshi Roy Justin J. Crowder Jon D. Piganelli Amelia K. Linnemann Amelia K. Linnemann |
| author_facet | Matthew C. Austin Charanya Muralidharan Saptarshi Roy Justin J. Crowder Jon D. Piganelli Amelia K. Linnemann Amelia K. Linnemann |
| author_sort | Matthew C. Austin |
| collection | DOAJ |
| description | BackgroundType 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune response in disease development. Previously, we discovered that β-cell autophagy is impaired prior to the onset of T1D, implicating this pathway in T1D pathogenesis.AimsTo assess the role of autophagy in β-cell health and survival, and whether defects in autophagy render islets more immunogenic.MethodsWe knocked out the critical autophagy enzyme, ATG7, in the β-cells of mice (ATG7Δβ-cell) then monitored blood glucose, performed glucose tolerance tests, and evaluated bulk islet mRNA and protein. We also assessed MHC-I expression and presence of CD45+ immune cells in ATG7Δβ-cell islets and evaluated how impaired autophagy affects EndoC-βH1 HLA-I expression under basal and IFNα stimulated conditions. Lastly, we co-cultured ATG7Δβ-cell islet cells with diabetogenic BDC2.5 helper T cells and evaluated T cell activation.ResultsWe found that all ATG7Δβ-cell mice developed diabetes between 11-15 weeks of age. Gene ontology analysis revealed a significant upregulation of pathways involved in inflammatory processes, response to ER stress, and the ER-associated degradation pathway. Interestingly, we also observed upregulation of proteins involved in MHC-I presentation, suggesting that defective β-cell autophagy may alter the immunopeptidome, or antigen repertoire, and enhance β-cell immune visibility. In support of this hypothesis, we observed increased MHC-I expression and CD45+ immune cells in ATG7Δβ-cell islets. We also demonstrate that HLA-I is upregulated in EndoC β-cells when autophagic degradation is inhibited. This effect was observed under both basal and IFNα stimulated conditions. Conversely, a stimulator of lysosome acidification/function, C381, decreased HLA-I expression. Lastly, we showed that in the presence of islet cells with defective autophagy, there is enhanced BDC2.5 T cell activation.ConclusionsOur findings demonstrate that β-cell autophagy is critical to cell survival/function. Defective β-cell autophagy induces ER stress, alters pathways of antigen production, and enhances MHC-I/HLA-I presentation to surveilling immune cells. Overall, our results suggest that defects in autophagy make β-cells more susceptible to immune attack and destruction. |
| format | Article |
| id | doaj-art-616342be08f740f1a10084a8523840b5 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-616342be08f740f1a10084a8523840b52025-01-29T06:45:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15045831504583Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicityMatthew C. Austin0Charanya Muralidharan1Saptarshi Roy2Justin J. Crowder3Jon D. Piganelli4Amelia K. Linnemann5Amelia K. Linnemann6Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United StatesIndiana Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, United StatesBackgroundType 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune response in disease development. Previously, we discovered that β-cell autophagy is impaired prior to the onset of T1D, implicating this pathway in T1D pathogenesis.AimsTo assess the role of autophagy in β-cell health and survival, and whether defects in autophagy render islets more immunogenic.MethodsWe knocked out the critical autophagy enzyme, ATG7, in the β-cells of mice (ATG7Δβ-cell) then monitored blood glucose, performed glucose tolerance tests, and evaluated bulk islet mRNA and protein. We also assessed MHC-I expression and presence of CD45+ immune cells in ATG7Δβ-cell islets and evaluated how impaired autophagy affects EndoC-βH1 HLA-I expression under basal and IFNα stimulated conditions. Lastly, we co-cultured ATG7Δβ-cell islet cells with diabetogenic BDC2.5 helper T cells and evaluated T cell activation.ResultsWe found that all ATG7Δβ-cell mice developed diabetes between 11-15 weeks of age. Gene ontology analysis revealed a significant upregulation of pathways involved in inflammatory processes, response to ER stress, and the ER-associated degradation pathway. Interestingly, we also observed upregulation of proteins involved in MHC-I presentation, suggesting that defective β-cell autophagy may alter the immunopeptidome, or antigen repertoire, and enhance β-cell immune visibility. In support of this hypothesis, we observed increased MHC-I expression and CD45+ immune cells in ATG7Δβ-cell islets. We also demonstrate that HLA-I is upregulated in EndoC β-cells when autophagic degradation is inhibited. This effect was observed under both basal and IFNα stimulated conditions. Conversely, a stimulator of lysosome acidification/function, C381, decreased HLA-I expression. Lastly, we showed that in the presence of islet cells with defective autophagy, there is enhanced BDC2.5 T cell activation.ConclusionsOur findings demonstrate that β-cell autophagy is critical to cell survival/function. Defective β-cell autophagy induces ER stress, alters pathways of antigen production, and enhances MHC-I/HLA-I presentation to surveilling immune cells. Overall, our results suggest that defects in autophagy make β-cells more susceptible to immune attack and destruction.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1504583/fulltype 1 diabetesautophagyβ-cell stressislet immunogenicityHLA-I expression |
| spellingShingle | Matthew C. Austin Charanya Muralidharan Saptarshi Roy Justin J. Crowder Jon D. Piganelli Amelia K. Linnemann Amelia K. Linnemann Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity Frontiers in Immunology type 1 diabetes autophagy β-cell stress islet immunogenicity HLA-I expression |
| title | Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity |
| title_full | Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity |
| title_fullStr | Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity |
| title_full_unstemmed | Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity |
| title_short | Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity |
| title_sort | dysfunctional β cell autophagy induces β cell stress and enhances islet immunogenicity |
| topic | type 1 diabetes autophagy β-cell stress islet immunogenicity HLA-I expression |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1504583/full |
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