Skip to main content
SpringerLink
Log in

Interferons are key cytokines acting on pancreatic islets in type 1 diabetes

  • Extended Article
  • Published:
Diabetologia Aims and scope Submit manuscript

Abstract

Aims/hypothesis

The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown.

Methods

We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes.

Results

IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to ‘danger signals’ such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells.

Conclusions/interpretation

These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

AAB1+:

One islet-specific autoantibody positive

AAB2+:

Two or more islet-specific autoantibodies positive

BACH2:

Basic leucine zipper transcription factor 2

CXCL10:

CXC motif chemokine ligand 10

DGE:

Differential gene expression

dIF:

Differential isoform fraction

dsRNA:

Double-stranded RNA

DTU:

Differential transcript usage

ER:

Endoplasmic reticulum

fGSEA:

Fast pre-ranked Gene set enrichment Analysis

GSEA:

Gene set enrichment analysis

HPAP:

Human Pancreas Analysis Program

ICI:

Insulin-containing islet

IDI:

Insulin-deficient islet

IL-1R:

IL-1 receptor

IRF:

IFN regulatory factor

ISG:

IFN-stimulated gene

JAK:

Janus kinase

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LARP1:

La ribonucleoprotein 1

PDL1:

Programmed Cell Death 1 Ligand 1

PIC:

Polyinosinic-polycytidylic acid

RRHO:

Rank–rank hypergeometric overlap

RT-qPCR:

Reverse transcription-quantitative PCR

STAT:

Signal transducer and activator of transcription

TYK2:

Tyrosine kinase 2

ZNFX1:

Zinc finger NFX1-type containing 1

References

  1. Eizirik DL, Pasquali L, Cnop M (2020) Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16(7):349–362. https://doi.org/10.1038/s41574-020-0355-7

    Article  CAS  PubMed  Google Scholar 

  2. Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383(9911):69–82. https://doi.org/10.1016/S0140-6736(13)60591-7

    Article  PubMed  Google Scholar 

  3. Mathieu C, Martens PJ, Vangoitsenhoven R (2021) One hundred years of insulin therapy. Nat Rev Endocrinol 17(12):715–725. https://doi.org/10.1038/s41574-021-00542-w

    Article  PubMed  Google Scholar 

  4. Ramos-Rodriguez M, Raurell-Vila H, Colli ML et al (2019) The impact of proinflammatory cytokines on the beta-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat Genet 51(11):1588–1595. https://doi.org/10.1038/s41588-019-0524-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Calderon B, Suri A, Pan XO, Mills JC, Unanue ER (2008) IFN-gamma-dependent regulatory circuits in immune inflammation highlighted in diabetes. J Immunol 181(10):6964–6974. https://doi.org/10.4049/jimmunol.181.10.6964

    Article  CAS  PubMed  Google Scholar 

  6. Colli ML, Ramos-Rodriguez M, Nakayasu ES et al (2020) An integrated multi-omics approach identifies the landscape of interferon-alpha-mediated responses of human pancreatic beta cells. Nat Commun 11(1):2584. https://doi.org/10.1038/s41467-020-16327-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Roca-Rivada A, Marin-Canas S, Colli ML et al (2023) Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF-alpha-induced human beta cell dysfunction and death. Diabetologia 66(8):1544–1556. https://doi.org/10.1007/s00125-023-05908-5

    Article  CAS  PubMed  Google Scholar 

  8. Ferreira RC, Guo H, Coulson RM et al (2014) A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes. Diabetes 63(7):2538–2550. https://doi.org/10.2337/db13-1777

    Article  PubMed  PubMed Central  Google Scholar 

  9. Marroqui L, Dos Santos RS, Op de Beeck A et al (2017) Interferon-alpha mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes. Diabetologia 60(4):656–667. https://doi.org/10.1007/s00125-016-4201-3

    Article  CAS  PubMed  Google Scholar 

  10. Richardson SJ, Pugliese A (2021) 100 years of insulin: Pancreas pathology in type 1 diabetes: an evolving story. J Endocrinol 252(2):R41–r57. https://doi.org/10.1530/joe-21-0358

    Article  CAS  PubMed  Google Scholar 

  11. Hu X, Li J, Fu M, Zhao X, Wang W (2021) The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 6(1):402. https://doi.org/10.1038/s41392-021-00791-1

    Article  PubMed  PubMed Central  Google Scholar 

  12. Eizirik DL, Szymczak F, Alvelos MI, Martin F (2021) From pancreatic beta-cell gene networks to novel therapies for type 1 diabetes. Diabetes 70(9):1915–1925. https://doi.org/10.2337/dbi20-0046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264. https://doi.org/10.1146/annurev.biochem.67.1.227

    Article  CAS  PubMed  Google Scholar 

  14. Tau G, Rothman P (1999) Biologic functions of the IFN-gamma receptors. Allergy 54(12):1233–1251. https://doi.org/10.1034/j.1398-9995.1999.00099.x

    Article  CAS  PubMed  Google Scholar 

  15. Achenbach P, Hippich M, Zapardiel-Gonzalo J et al (2022) A classification and regression tree analysis identifies subgroups of childhood type 1 diabetes. EBioMedicine 82:104118. https://doi.org/10.1016/j.ebiom.2022.104118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nicoletti F, Zaccone P, Di Marco R et al (1996) The effects of a nonimmunogenic form of murine soluble interferon-gamma receptor on the development of autoimmune diabetes in the NOD mouse. Endocrinology 137(12):5567–5575. https://doi.org/10.1210/endo.137.12.8940385

    Article  CAS  PubMed  Google Scholar 

  17. Debray-Sachs M, Carnaud C, Boitard C et al (1991) Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun 4(2):237–248. https://doi.org/10.1016/0896-8411(91)90021-4

    Article  CAS  PubMed  Google Scholar 

  18. De George DJ, Ge T, Krishnamurthy B, Kay TWH, Thomas HE (2023) Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis. Front Cell Dev Biol 11:1205590. https://doi.org/10.3389/fcell.2023.1205590

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107. https://doi.org/10.2337/diabetes.54.suppl_2.s97

    Article  CAS  PubMed  Google Scholar 

  20. Brozzi F, Nardelli TR, Lopes M et al (2015) Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia 58(10):2307–2316. https://doi.org/10.1007/s00125-015-3669-6

    Article  CAS  PubMed  Google Scholar 

  21. Szymczak F, Colli ML, Mamula MJ, Evans-Molina C, Eizirik DL (2021) Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Sci Adv 7(2). https://doi.org/10.1126/sciadv.abd7600

  22. Ravassard P, Hazhouz Y, Pechberty S et al (2011) A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion. J Clin Invest 121(9):3589–3597. https://doi.org/10.1172/JCI58447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nacher M, Estil LE, Garcia A et al (2016) Human serum versus human serum albumin supplementation in human islet pretransplantation culture: in vitro and in vivo assessment. Cell Transplant 25(2):343–352. https://doi.org/10.3727/096368915X688119

    Article  PubMed  Google Scholar 

  24. Marchetti P, Dotta F, Lauro D, Purrello F (2008) An overview of pancreatic beta-cell defects in human type 2 diabetes: implications for treatment. Regul Pept 146(1-3):4–11. https://doi.org/10.1016/j.regpep.2007.08.017

    Article  CAS  PubMed  Google Scholar 

  25. Gennady K, Vladimir S, Nikolay B, Boris S, Maxim NA, Alexey S (2021) Fast gene set enrichment analysis. bioRxiv:060012. https://doi.org/10.1101/060012

  26. Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30. https://doi.org/10.1093/nar/28.1.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fabregat A, Jupe S, Matthews L et al (2018) The reactome pathway knowledgebase. Nucleic Acids Res 46(D1):D649–D655. https://doi.org/10.1093/nar/gkx1132

    Article  CAS  PubMed  Google Scholar 

  28. Plaisier SB, Taschereau R, Wong JA, Graeber TG (2010) Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res 38(17):e169. https://doi.org/10.1093/nar/gkq636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Piron A, Szymczak F, Papadopoulou T et al (2024) RedRibbon: A new rank-rank hypergeometric overlap for gene and transcript expression signatures. Life Sci Alliance 7(2). https://doi.org/10.26508/lsa.202302203

  30. Russell MA, Redick SD, Blodgett DM et al (2019) HLA class II antigen processing and presentation pathway components demonstrated by transcriptome and protein analyses of islet beta-cells from donors with type 1 diabetes. Diabetes 68(5):988–1001. https://doi.org/10.2337/db18-0686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Moore F, Colli ML, Cnop M et al (2009) PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis. Diabetes 58(6):1283–1291. https://doi.org/10.2337/db08-1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hoorens A, Van de Casteele M, Kloppel G, Pipeleers D (1996) Glucose promotes survival of rat pancreatic beta cells by activating synthesis of proteins which suppress a constitutive apoptotic program. J Clin Invest 98(7):1568–1574. https://doi.org/10.1172/JCI118950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Szymczak F, Alvelos MI, Marin-Canas S et al (2022) Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic beta cells. Sci Adv 8(37):eabn5732. https://doi.org/10.1126/sciadv.abn5732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vitting-Seerup K, Sandelin A (2019) IsoformSwitchAnalyzeR: analysis of changes in genome-wide patterns of alternative splicing and its functional consequences. Bioinformatics 35(21):4469–4471. https://doi.org/10.1093/bioinformatics/btz247

    Article  CAS  PubMed  Google Scholar 

  35. Gonzalez-Duque S, Azoury ME, Colli ML et al (2018) Conventional and neo-antigenic peptides presented by beta cells are targeted by circulating naive CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab 28(6):946–960 e946. https://doi.org/10.1016/j.cmet.2018.07.007

  36. Verstrepen L, Verhelst K, van Loo G, Carpentier I, Ley SC, Beyaert R (2010) Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem Pharmacol 80(12):2009–2020. https://doi.org/10.1016/j.bcp.2010.06.044

    Article  CAS  PubMed  Google Scholar 

  37. Villate O, Turatsinze JV, Mascali LG et al (2014) Nova1 is a master regulator of alternative splicing in pancreatic beta cells. Nucleic Acids Res 42(18):11818–11830. https://doi.org/10.1093/nar/gku861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Roep BO, Kracht MJ, van Lummel M, Zaldumbide A (2016) A roadmap of the generation of neoantigens as targets of the immune system in type 1 diabetes. Curr Opin Immunol 43:67–73. https://doi.org/10.1016/j.coi.2016.09.007

    Article  CAS  PubMed  Google Scholar 

  39. Pugliese A (2017) Autoreactive T cells in type 1 diabetes. J Clin Invest 127(8):2881–2891. https://doi.org/10.1172/JCI94549

    Article  PubMed  PubMed Central  Google Scholar 

  40. Eizirik DL, Colli ML (2020) Revisiting the role of inflammation in the loss of pancreatic beta-cells in T1DM. Nat Rev Endocrinol 16(11):611–612. https://doi.org/10.1038/s41574-020-00409-6

    Article  PubMed  Google Scholar 

  41. Mallone R, Eizirik DL (2020) Presumption of innocence for beta cells: why are they vulnerable autoimmune targets in type 1 diabetes? Diabetologia 63(10):1999–2006. https://doi.org/10.1007/s00125-020-05176-7

    Article  PubMed  Google Scholar 

  42. Bender C, Rajendran S, von Herrath MG (2020) New insights into the role of autoreactive CD8 T cells and cytokines in human type 1 diabetes. Front Endocrinol (Lausanne) 11:606434. https://doi.org/10.3389/fendo.2020.606434

    Article  PubMed  Google Scholar 

  43. Colli ML, Hill JLE, Marroquí L et al (2018) PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction. EBioMedicine 36:367–375. https://doi.org/10.1016/j.ebiom.2018.09.040

    Article  PubMed  PubMed Central  Google Scholar 

  44. Richardson SJ, Rodriguez-Calvo T, Gerling IC et al (2016) Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59(11):2448–2458. https://doi.org/10.1007/s00125-016-4067-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Christen U, Kimmel R (2020) Chemokines as drivers of the autoimmune destruction in type 1 diabetes: opportunity for therapeutic intervention in consideration of an optimal treatment schedule. Front Endocrinol (Lausanne) 11:591083. https://doi.org/10.3389/fendo.2020.591083

    Article  PubMed  Google Scholar 

  46. Colli ML, Szymczak F, Eizirik DL (2020) Molecular footprints of the immune assault on pancreatic beta cells in type 1 diabetes. Front Endocrinol (Lausanne) 11:568446. https://doi.org/10.3389/fendo.2020.568446

    Article  PubMed  Google Scholar 

  47. Wyatt RC, Lanzoni G, Russell MA, Gerling I, Richardson SJ (2019) What the HLA-I!—classical and non-classical HLA class I and their potential roles in type 1 diabetes. Curr Diab Rep 19(12):159. https://doi.org/10.1007/s11892-019-1245-z

  48. Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG (2013) Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 56(1):185–193. https://doi.org/10.1007/s00125-012-2745-4

    Article  CAS  PubMed  Google Scholar 

  49. Krogvold L, Leete P, Mynarek IM et al (2022) Detection of antiviral tissue responses and increased cell stress in the pancreatic islets of newly diagnosed type 1 diabetes patients: Results from the DiViD study. Front Endocrinol 13. https://doi.org/10.3389/fendo.2022.881997

  50. Ramos-Rodríguez M, Pérez-González B, Pasquali L (2021) The β-cell genomic landscape in T1D: implications for disease pathogenesis. Curr Diab Rep 21(1):1. https://doi.org/10.1007/s11892-020-01370-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Santin I, Eizirik DL (2013) Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis. Diabetes Obes Metab 15(Suppl 3):71–81. https://doi.org/10.1111/dom.12162

    Article  CAS  PubMed  Google Scholar 

  52. Marroquí L, Santin I, Dos Santos RS, Marselli L, Marchetti P, Eizirik DL (2014) BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic β-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2. Diabetes 63(7):2516–2527. https://doi.org/10.2337/db13-1443

    Article  PubMed  Google Scholar 

  53. Wang Y, Yuan S, Jia X et al (2019) Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS. Nat Cell Biol 21(11):1346–1356. https://doi.org/10.1038/s41556-019-0416-0

    Article  CAS  PubMed  Google Scholar 

  54. Foulis AK, Farquharson MA, Meager A (1987) Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2(8573):1423–1427. https://doi.org/10.1016/s0140-6736(87)91128-7

    Article  CAS  PubMed  Google Scholar 

  55. Coomans de Brachene A, Castela A, Op de Beeck A et al (2020) Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta-cell protection in type 1 diabetes. Diabetes Obes Metab 22(10):1827–1836. https://doi.org/10.1111/dom.14104

    Article  CAS  PubMed  Google Scholar 

  56. Chandra V, Ibrahim H, Halliez C et al (2022) The type 1 diabetes gene TYK2 regulates beta-cell development and its responses to interferon-alpha. Nat Commun 13(1):6363. https://doi.org/10.1038/s41467-022-34069-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Waibel M, Wentworth JM, So M et al (2023) Baricitinib and beta-cell function in patients with new-onset type 1 diabetes. N Engl J Med 389(23):2140–2150. https://doi.org/10.1056/NEJMoa2306691

    Article  CAS  PubMed  Google Scholar 

  58. Moran A, Bundy B, Becker DJ et al (2013) Interleukin-1 antagonism in type 1 diabetes of recent onset: Two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381(9881):1905–1915. https://doi.org/10.1016/S0140-6736(13)60023-9

    Article  CAS  PubMed  Google Scholar 

  59. Quattrin T, Haller MJ, Steck AK et al (2020) Golimumab and beta-cell function in youth with new-onset type 1 diabetes. N Engl J Med 383(21):2007–2017. https://doi.org/10.1056/NEJMoa2006136

    Article  CAS  PubMed  Google Scholar 

  60. Rigby MR, Hayes B, Li Y, Vercruysse F, Hedrick JA, Quattrin T (2023) Two-year follow-up from the T1GER study: Continued off-therapy metabolic improvements in children and young adults with new-onset T1D treated with golimumab and characterization of responders. Diabetes Care 46(3):561–569. https://doi.org/10.2337/dc22-0908

    Article  CAS  PubMed  Google Scholar 

  61. Mastrandrea L, Yu J, Behrens T et al (2009) Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32(7):1244–1249. https://doi.org/10.2337/dc09-0054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ludvigsson J, Routray I, Vigard T et al (2021) Combined etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes. Diabetes Metab Res Rev 37(7):e3440. https://doi.org/10.1002/dmrr.3440

    Article  CAS  PubMed  Google Scholar 

  63. Lee LF, Xu B, Michie SA et al (2005) The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. Proc Natl Acad Sci U S A 102(44):15995–16000. https://doi.org/10.1073/pnas.0508122102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wu AJ, Hua H, Munson SH, McDevitt HO (2002) Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc Natl Acad Sci U S A 99(19):12287–12292. https://doi.org/10.1073/pnas.172382999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Son J, Ding H, Farb TB et al (2021) BACH2 inhibition reverses beta cell failure in type 2 diabetes models. J Clin Invest 131(24). https://doi.org/10.1172/JCI153876

  66. Nekoua MP, Alidjinou EK, Hober D (2022) Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 18(8):503–516. https://doi.org/10.1038/s41574-022-00688-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Op de Beeck A, Eizirik DL (2016) Viral infections in type 1 diabetes mellitus — why the β cells? Nat Rev Endocrinol 12(5):263–273. https://doi.org/10.1038/nrendo.2016.30

    Article  CAS  PubMed Central  Google Scholar 

  68. Nigi L, Brusco N, Grieco GE et al (2022) Increased expression of viral sensor MDA5 in pancreatic islets and in hormone-negative endocrine cells in recent onset type 1 diabetic donors. Front Immunol 13. https://doi.org/10.3389/fimmu.2022.833141

  69. Colli ML, Moore F, Gurzov EN, Ortis F, Eizirik DL (2010) MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA. Hum Mol Genet 19(1):135–146. https://doi.org/10.1093/hmg/ddp474

    Article  CAS  PubMed  Google Scholar 

  70. Juan-Mateu J, Alvelos MI, Turatsinze JV et al (2018) SRp55 regulates a splicing network that controls human pancreatic beta-cell function and survival. Diabetes 67(3):423–436. https://doi.org/10.2337/db17-0736

    Article  CAS  PubMed  Google Scholar 

  71. Barclay AN, Van den Berg TK (2014) The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32:25–50. https://doi.org/10.1146/annurev-immunol-032713-120142

    Article  CAS  PubMed  Google Scholar 

  72. Leslie KA, Richardson SJ, Russell MA, Morgan NG (2021) Expression of CD47 in the pancreatic β-cells of people with recent-onset type 1 diabetes varies according to disease endotype. Diabet Med 38(12):e14724. https://doi.org/10.1111/dme.14724

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Alexandra Coomans de Brachène, Maria Ines Alvelos and Florian Szymczak contributed equally to this study.

Authors and Affiliations

  1. ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium

    Alexandra Coomans de Brachène, Maria Ines Alvelos, Florian Szymczak, Priscila L. Zimath, Angela Castela, Bianca Marmontel de Souza, Arturo Roca Rivada, Sandra Marín-Cañas, Xiaoyan Yi, Anne Op de Beeck & Decio L. Eizirik

  2. Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK

    Noel G. Morgan & Sarah J. Richardson

  3. InSphero AG, Schlieren, Switzerland

    Sebastian Sonntag, Sayro Jawurek, Alexandra C. Title & Burcak Yesildag

  4. University of Applied Sciences and Arts Northwestern Switzerland, Basel, Switzerland

    Sebastian Sonntag

  5. European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France

    François Pattou & Julie Kerr-Conte

  6. Hospital Universitari Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and University of Barcelona, Barcelona, Spain

    Eduard Montanya & Montserrat Nacher

  7. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Lorella Marselli & Piero Marchetti

Authors
  1. Alexandra Coomans de Brachène
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Ines Alvelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florian Szymczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Priscila L. Zimath
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angela Castela
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bianca Marmontel de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arturo Roca Rivada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandra Marín-Cañas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoyan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anne Op de Beeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Noel G. Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sebastian Sonntag
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sayro Jawurek
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alexandra C. Title
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Burcak Yesildag
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. François Pattou
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Julie Kerr-Conte
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Eduard Montanya
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Montserrat Nacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Lorella Marselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Piero Marchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sarah J. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Decio L. Eizirik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alexandra Coomans de Brachène or Decio L. Eizirik.

Ethics declarations

Acknowledgements

The authors are grateful to A. M. Musuaya, L. Sauvage, Y. Cai and I. Millard of the ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgium, for excellent technical support, and to J. Hopkinson, C. Flaxman, J. Hill, R. Wyatt, M. Russell and K. Murrall from EXCEED for imaging assistance.

Data availability

All data are available in the main text or the electronic supplementary material (ESM). They are available from the corresponding authors upon reasonable request. All newly generated RNA-seq data that support the findings of the present study have been deposited at GEO under accession code GSE235683.

Funding

DLE acknowledges the support of grants from JDRF International (3-SRA-2022-1201-S-B [1] and 3-SRA-2022-1201-S-B [2]); Welbio-FNRS (Fonds National de la Recherche Scientifique) (WELBIO-CR-2019C-04), Belgium; the Dutch Diabetes Research Foundation (Innovate2CureType1), Holland; JDRF (3-SRA-2022-1201-S-B); the National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786); and the National Institutes of Health NIDDK grants RO1DK126444 and RO1DK133881-01. DLE, PM, SJR and NGM acknowledge support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 (INNODIA) and 945268 (INNODIA HARVEST). These joint undertakings receive support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA), JDRF and The Leona M. and Harry B. Helmsley Charitable Trust. FS is supported by a Research Fellow (Aspirant) fellowship from the FNRS (Belgium). XY is supported by the Fondation ULB, Wallonie-Bruxelles International (WBI) and the China Scholarship Council. AOdB is supported by a grant (CDR) from the FNRS (35248676). EM acknowledges the support of grants PI19/00246 and PI22/00334 from Instituto de Salud Carlos III, co-financed by the European Regional Development Fund (ERCF). Parts of this study were supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Authors’ relationships and activities

SS, SJ and ACT are or were employees of InSphero AG, a company commercialising islet microtissues and related services. BY is a member of the management team of InSphero AG. DLE is a member of the Scientific Advisory Board of InSphero AG. PM is a member of the editorial board of Diabetologia. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

ACdB, MIA and FS contributed to the original idea; to the design, performance and interpretation of the experiments; and to the investigation and formal analysis; and wrote, revised and edited the manuscript. PLZ performed and analysed experiments, and wrote, revised and edited the manuscript. AC, BMdS, SJR, NGM, ARR, SM-C, XY, AOdB, SS, SJ, ACT and BY performed and analysed experiments. FP, JK-C, EM, MN, LM and PM contributed with material and acquisition of data. DLE contributed to the original idea and the design, supervision and interpretation of the experiments, and wrote and revised the manuscript. All authors have read and approved the final version of the manuscript. ACdB, MIA and DLE are the guarantors of this work and, as such, have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1836 KB)

Supplementary file2 (PDF 2167 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Coomans de Brachène, A., Alvelos, M.I., Szymczak, F. et al. Interferons are key cytokines acting on pancreatic islets in type 1 diabetes. Diabetologia 67, 908–927 (2024). https://doi.org/10.1007/s00125-024-06106-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00125-024-06106-7

Keywords

Search

Navigation