NF-kappa B; Protein Serine-Threonine Kinases; Animals; Mice; NF-kappa B/metabolism; Protein Serine-Threonine Kinases/genetics; Signal Transduction/physiology; NF-kappaB-Inducing Kinase; Diabetes Mellitus/pathology; Insulin-Secreting Cells/metabolism; Diabetes Mellitus; Insulin-Secreting Cells; Signal Transduction; Immunology; Cellular and Molecular Neuroscience; Cell Biology; Cancer Research
Abstract :
[en] The transcription factor nuclear factor-κB (NF-κB) has a key role in the pathogenesis of diabetes and its complications. Although activation of the canonical NF-κB pathway in β-cells is generally deleterious, little is known about the role of the non-canonical NF-κB signalling and its main regulator, the NF-κB-inducing kinase (NIK), on pancreatic β-cell survival and function. Previous studies based on models of NIK overexpression in pancreatic islet cells showed that NIK induced either spontaneous β-cell death due to islet inflammation or glucose intolerance during diet-induced obesity (DIO) in mice. Therefore, NIK has been proposed as a potential target for diabetes therapy. However, no clear studies showed whether inhibition of NIK improves diabetes development. Here we show that genetic silencing of NIK in pancreatic β-cells neither modifies diabetes incidence nor inflammatory responses in a mouse model of immune-mediated diabetes. Moreover, NIK silencing in DIO mice did not influence body weight gain, nor glucose metabolism. In vitro studies corroborated the in vivo findings in terms of β-cell survival, function, and downstream gene regulation. Taken together, our data suggest that NIK activation is dispensable for the development of diabetes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Xiao, Peng; Inflammation and Cell Death Signalling group, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
Takiishi, Tatiana; Inflammation and Cell Death Signalling group, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
Violato, Natalia Moretti; Inflammation and Cell Death Signalling group, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
Licata, Giada; Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy ; Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
Dotta, Francesco; Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy ; Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy ; Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
Sebastiani, Guido; Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy ; Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
Marselli, Lorella; Department of Clinical and Experimental Medicine, Islet Laboratory, University of Pisa, Pisa, Italy
Singh, Sumeet Pal; Institute for Interdisciplinary Research in Human and Molecular Biology, Medical Faculty, Université libre de Bruxelles, Brussels, Belgium
Sze, Mozes; Center for Inflammation Research, VIB, B-9052, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, B-9052, Ghent, Belgium
Van Loo, Geert ; Center for Inflammation Research, VIB, B-9052, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, B-9052, Ghent, Belgium
Dejardin, Emmanuel ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Molecular Immunology and Signal Transduction
Gurzov, Esteban Nicolas ; Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium
Cardozo, Alessandra Kupper ; Inflammation and Cell Death Signalling group, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Brussels, Belgium. alessandra.kupper.cardozo@ulb.ac.be
We thank A. Musuaya, C. Dubois and M. Popa for technical assistance. Work in the AKC and ED groups were supported by the Excellence of Science grant (FNRS, Belgium, convention 30826052). FD is supported by the Italian Ministry of University and Research (2268-2019-DF-CONRICMIUR PRIN2017_001) and by the Italian Ministry of Health (PROMETEO). GS was supported by the Italian Ministry of University and Research (201793XZ5A_006) and by the Italian Ministry of Health “Ricerca Finalizzata 2018” (GR-2018-12365577). Work in SPS’s lab was supported by MISU (34772792) and MISU-PROL (40005588) funding from the FNRS and from Fondation Jaumotte-Demoulin. ENG is supported by a Fonds National de la Recherche Scientifique (FNRS)-MIS grant (33650793), an FNRS-CDR grant (35275350), a European Research Council (ERC) Consolidator grant METAPTPs (GA817940), and a JDRF Career Development Award (CDA-2019-758-A-N). ENG is a Research Associate of the FNRS, Belgium.
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