SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Beyaert, Rudi

Cardozo, AK

Catrysse, Leen

Fukaya, M

Meyerovich, K

Sze, Mozes

van Loo, Geert

Cell Death and Disease

English

PubMed

Fukaya, Makiko

Sze, M

Meyerovich, Kira

Cardozo, Alessandra K

Van Loo, Geert

DI-fusion

A20 deficiency sensitizes pancreatic beta cells to cytokine-induced apoptosis in vitro but does not influence type 1 diabetes development in vivo.

Ghent University Academic Bibliography

OPENCorrespondenceA20 deficiency sensitizes pancreatic beta cells tocytokine-induced apoptosis in vitro but does notinfluence type 1 diabetes development in vivoL Catrysse1,2, M Fukaya3, M Sze1,2, K Meyerovich3, R Beyaert1,2, AK Cardozo3 and G van Loo*,1,2Cell Death and Disease (2015) 6, e1918; doi:10.1038/cddis.2015.301; published online 15 October 2015Dear Editor,Type 1 diabetes mellitus (T1D) is an autoimmune diseasecharacterized by the infiltration of inflammatory cells into thepancreatic islets of Langerhans, followed by the selectivedestruction of insulin-producing β-cells, resulting inhyperglycemia. One of the mechanisms causing β-cell deathis the intra-islet release of inflammatory mediators suchas interleukin-1β (IL-1β), tumor necrosis factor (TNF)and interferon-γ (IFN-γ) by activated immune cells.1 Hence,the transcription factor NF-κB promotes pro-inflammatoryand pro-apoptotic responses in β-cells on cytokine exposure.A transgenic mouse line in which NF-κB activation isattenuated specifically in β-cells conferred nearly completeprotection against multiple low dose streptozotocin(MLDSTZ)-induced T1D.2 Contrary, mice with constitutivelyactive NF-κB signaling in β-cells spontaneously developfull-blown immune-mediated diabetes.3The ubiquitin-editing enzyme A20 is a critical negativeregulator of NF-κB signaling in response to multiple stimuli,including TNF and IL-1. Moreover, A20 can also act as astrong anti-apoptotic protein in specific cell types.4 A20 hasbeen identified as the most highly upregulated anti-apoptoticprotein in cytokine-stimulated primary islets and insulinomacell lines.5 Consistent with this, overexpression of A20 inislets confers resistance to cytokine-mediated activation ofNF-κB, protecting them from apoptosis in the early post-transplantation period.6 Interestingly, not only have NF-κBpolymorphisms been identified in patients with T1D,7 alsoA20/TNFAIP3 has been identified as a T1D susceptibilitylocus in humans.8 Together, these data suggest an importantrole for A20 in β-cell function and T1D. Therefore, wegenerated and characterized A20-deficient mice which lackexpression of A20 specifically in β-cells (SupplementaryFigure 1A).We first confirmed the anti-apoptotic function of A20 inβ-cells, as primary islets isolated from β-cell-specificA20 knockout (A20β−KO) mice were more susceptibleto cytokine-induced cell death compared with wild-typeislets (Supplementary Figure 1A). As A20 has a crucial role inβ-cell survival in vitro, we next investigated whetherA20β-KO mice would be more susceptible to diabetesdevelopment when compared with wild-type littermates.A20β-KO mice aged normally without any evidence ofmetabolic defects. Phenotypic analysis of A20β-KO mice upto the age of 12 months revealed no pathological signsin the pancreas. A20β-KO mice and control littermateswere subjected to a model of T1D induced by MLDSTZ,however, both control and A20β-KO mice developed asimilar hyperglycemia, which was confirmed in a glucosetolerance test (ipGTT) performed 5 weeks after the first STZinjection (Supplementary Figure 1B). Next, we crossedA20β-KO mice with C57BL6-Ins2Akita/J mice, which carry amutation in the insulin Ins2 gene that prevents normal foldingand secretion and induces endoplasmic reticulum stressleading to β-cell death. Mice carrying the Ins2Akita mutationbecome hyperglycemic very early in life, however, nodifferences could be observed in conditions of A20 deficiencyin β cells. In agreement, ipGTT shows severe and similardefects in insulin secretion in both Ins2Akita and A20β−KO/Akitamice (Supplementary Figure 1C). Finally, A20β-KO micewere backcrossed into a non-obese diabetic geneticbackground, and glucose levels were measured everyweek in order to follow diabetes development. Althoughonly 40% of all mice developed diabetes, no differencescould be detected between control and A20β-KO mice(Supplementary Figure 1D). In conclusion, A20 deficiencyin β cells does not affect β-cell apoptosis nor diseasedevelopment in vivo.Conflict of InterestThe authors declare no conflict of interest.Acknowledgements. L. Catrysse is a PhD fellow with the ‘Instituut voorInnovatie door Wetenschap en Technologie’ (IWT). AK. Cardozo is a researchassociate with the Fonds de la Recherche Scientifique (FNRS)-Belgium. Researchin the authors’ lab was supported by grants from the FWO, the ‘Belgian Foundationagainst Cancer’, the ‘Geneeskundige Stichting Koningin Elisabeth’, the CharcotFoundation, the GOA and ‘Group-ID MRP’ of the Ghent University, the Juvenile1Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, B-9052 Ghent, Belgium; 2Department of Biomedical Molecular Biology, GhentUniversity, B-9052 Ghent, Belgium and 3ULB Center for Diabetes Research, Université Libre de Bruxelles, B-1070 Brussels, Belgium*Corresponding author: G van Loo, Department of Biomedical Molecular Biology, Inflammation Research Center, VIB and Ghent University, Technologiepark 927,B-9052 Ghent, Belgium. Tel: 003293313761; Fax: 003292217673; E-mail: geert.vanloo@irc.vib-ugent.beCitation: Cell Death and Disease (2015) 6, e1918; doi:10.1038/cddis.2015.301& 2015 Macmillan Publishers Limited All rights reserved 2041-4889/15www.nature.com/cddisDiabetes Foundation, the Actions de Recherche Concertées (ARC)-ULB andthe FNRS.1. Mathis D et al. Nature 2001; 414: 792–798.2. Eldor R et al. Proc Natl Acad Sci USA 2006; 103: 5072–5077.3. Salem HH et al. Diabetes 2014; 63: 960–975.4. Catrysse L et al. Trends Immunol 2014; 35: 22–31.5. Liuwantara D et al. Diabetes 2006; 55: 2491–2501.6. Grey ST et al. J Immunol 2003; 170: 6250–6256.7. Hegazy DM et al. Genes Immun 2001; 2: 304–308.8. Fung EY et al. Genes Immun 2009; 10: 188–191.Cell Death and Disease is an open-access journalpublished by Nature Publishing Group. This work islicensed under a Creative Commons Attribution 4.0 InternationalLicense. The images or other third party material in this article areincluded in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under theCreative Commons license, users will need to obtain permission fromthe license holder to reproduce the material. To view a copy of thislicense, visit http://creativecommons.org/licenses/by/4.0/Supplementary Information accompanies this paper on Cell Death and Disease website (http://www.nature.com/cddis)Correspondence2Cell Death and Disease

A20 deficiency sensitizes pancreatic beta cells to cytokine-induced apoptosis in vitro but does not influence type 1 diabetes development in vivo

A20 deficiency sensitizes pancreatic beta cells to cytokine-induced apoptosis in vitro but does not influence type 1 diabetes development in vivo

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