Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context
Summary: Background: Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune c...
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Elsevier
2025-07-01
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| author | Farooq Syed Olivia Ballew Chih-Chun Lee Jyoti Rana Preethi Krishnan Angela Castela Staci A. Weaver Namratha Shivani Chalasani Sofia F. Thomaidou Stephane Demine Garrick Chang Alexandra Coomans de Brachène Maria Ines Alvelos Eugenia Martin Vazquez Lorella Marselli Kara Orr Jamie L. Felton Jing Liu John S. Kaddis Piero Marchetti Arnaud Zaldumbide Donalyn Scheuner Decio L. Eizirik Carmella Evans-Molina |
| author_facet | Farooq Syed Olivia Ballew Chih-Chun Lee Jyoti Rana Preethi Krishnan Angela Castela Staci A. Weaver Namratha Shivani Chalasani Sofia F. Thomaidou Stephane Demine Garrick Chang Alexandra Coomans de Brachène Maria Ines Alvelos Eugenia Martin Vazquez Lorella Marselli Kara Orr Jamie L. Felton Jing Liu John S. Kaddis Piero Marchetti Arnaud Zaldumbide Donalyn Scheuner Decio L. Eizirik Carmella Evans-Molina |
| author_sort | Farooq Syed |
| collection | DOAJ |
| description | Summary: Background: Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune conditions. Methods: We evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human β cells, cadaveric islets, iPSC-derived islets, and mouse models. Findings: In vitro studies showed that TYK2is prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with TYK2i prevented IFNα-induced antigenic peptide presentation and alloreactive and autoreactive T cell degranulation. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP and NOD mice) reduced systemic and tissue-localised inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes, and spleen highlighted a role for TYK2 inhibition in modulating signalling pathways associated with inflammation, translational control, stress signalling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues. Interpretation: These findings indicate that TYK2i has beneficial effects on both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2is in human T1D. Funding: This work was supported by the National Institutes of Health (NIH), Veteran Affairs (VA), Breakthrough T1D, and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation. |
| format | Article |
| id | doaj-art-b514f20ccda346bf88ef0642630d3313 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-b514f20ccda346bf88ef0642630d33132025-08-20T03:25:05ZengElsevierEBioMedicine2352-39642025-07-0111710573410.1016/j.ebiom.2025.105734Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in contextFarooq Syed0Olivia Ballew1Chih-Chun Lee2Jyoti Rana3Preethi Krishnan4Angela Castela5Staci A. Weaver6Namratha Shivani Chalasani7Sofia F. Thomaidou8Stephane Demine9Garrick Chang10Alexandra Coomans de Brachène11Maria Ines Alvelos12Eugenia Martin Vazquez13Lorella Marselli14Kara Orr15Jamie L. Felton16Jing Liu17John S. Kaddis18Piero Marchetti19Arnaud Zaldumbide20Donalyn Scheuner21Decio L. Eizirik22Carmella Evans-Molina23Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Diabetes-Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USAIndiana Biosciences Research Institute, Indianapolis, IN, USAIndiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USAIndiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USAIndiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USAULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumIndiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USAIndiana University School of Medicine, Indianapolis, IN, USADepartment of Cell and Chemical Biology, Leiden University Medical Center, the NetherlandsIndiana Biosciences Research Institute, Indianapolis, IN, USADepartment of Physics, Indiana University Indianapolis, Indianapolis, IN, USAULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumDepartment of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyIndiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USAIndiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Physics and Astronomy, Purdue University, West Lafayette, IN, USADepartment of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USADepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyDepartment of Cell and Chemical Biology, Leiden University Medical Center, the NetherlandsIndiana Biosciences Research Institute, Indianapolis, IN, USAULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium; Corresponding author.Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA; Corresponding author. Indiana University School of Medicine, 1210 Waterway Blvd, 4108G, Indianapolis, IN 46202, USA.Summary: Background: Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune conditions. Methods: We evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human β cells, cadaveric islets, iPSC-derived islets, and mouse models. Findings: In vitro studies showed that TYK2is prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with TYK2i prevented IFNα-induced antigenic peptide presentation and alloreactive and autoreactive T cell degranulation. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP and NOD mice) reduced systemic and tissue-localised inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes, and spleen highlighted a role for TYK2 inhibition in modulating signalling pathways associated with inflammation, translational control, stress signalling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues. Interpretation: These findings indicate that TYK2i has beneficial effects on both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2is in human T1D. Funding: This work was supported by the National Institutes of Health (NIH), Veteran Affairs (VA), Breakthrough T1D, and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation.http://www.sciencedirect.com/science/article/pii/S2352396425001781Type 1 diabetesβ cellT cellIslets of langerhansTyrosine protein-kinase 2 (TYK2)Interferon-α |
| spellingShingle | Farooq Syed Olivia Ballew Chih-Chun Lee Jyoti Rana Preethi Krishnan Angela Castela Staci A. Weaver Namratha Shivani Chalasani Sofia F. Thomaidou Stephane Demine Garrick Chang Alexandra Coomans de Brachène Maria Ines Alvelos Eugenia Martin Vazquez Lorella Marselli Kara Orr Jamie L. Felton Jing Liu John S. Kaddis Piero Marchetti Arnaud Zaldumbide Donalyn Scheuner Decio L. Eizirik Carmella Evans-Molina Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context EBioMedicine Type 1 diabetes β cell T cell Islets of langerhans Tyrosine protein-kinase 2 (TYK2) Interferon-α |
| title | Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context |
| title_full | Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context |
| title_fullStr | Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context |
| title_full_unstemmed | Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context |
| title_short | Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceResearch in context |
| title_sort | pharmacological inhibition of tyrosine protein kinase 2 reduces islet inflammation and delays type 1 diabetes onset in miceresearch in context |
| topic | Type 1 diabetes β cell T cell Islets of langerhans Tyrosine protein-kinase 2 (TYK2) Interferon-α |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425001781 |
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