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The role of NF-κB-inducing kinase (NIK) in beta cell-mediated inflammation in type 1 diabetes

par Xiao, Peng ;Takiishi, Tatiana ;Moretti Violato, Natalia ;Licata, Giada;Dotta, Francesco;Sebastiani, Guido;Cardozo, Alessandra K
Référence 56th EASD Annual Meeting of the European Association for the Study of Diabetes, Diabetologia, 63(Suppl 1):1-485
Publication Publié, 2020-09-21

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Résumé :

Background and aims: In type 1 diabetes (T1D) β-cell destruction results from an aberrant inflammatory crosstalk between the β-cells and immune-cells mediated, partly, via activation of the transcription factor NF-κB. NF-κB signaling occurs via two major pathways called canonical and the alternative. The alternative pathway is characterized by stabiliza- tion of the NF-κB-inducing kinase (NIK) triggering p100 processing into p52, which dimerizes with RelB to regulate gene transcription. The canonical NF-κB pathway was shown to contribute to β-cell death in T1D, however, the role of the alternative pathway in T1D is unknown. Ligands that activate the alternative pathway (e.g. LIGHT, CD40L) are present in the serum of T1D patients and are involved in pathogenesis in non-obese diabetic mice. We previously identified that in vitro cytokine treatment, which induces β-cell death, promotes NIK stabilization and activation of downstream NF-κB signaling in rat β-cells. Thus, the aim of this study is to characterize the role of NIK in β-cell demise during T1D and its regulation on peripheral and local immune responses.Materials and methods: To evaluate the role of NIK specifically in β- cells we developed a β-cell specific NIK KO mouse (NIKβKO). To verify if lack of NIK in β-cells affects its development and function we followed NIKβKO mice and wild type littermates (WT) up to 24 weeks. Mouse glycemia and bodyweight were measured weekly and intraperitoneal glucose tolerance tests (ipGTT) were performed at 12 and 24 weeks of age. Insulin content of the islets were measured when mice were eutha- nized. To induce T1D, mice were injected with multiple low doses of streptozotocin (MLDSTZ). Mice were sacrificed 14 and 45 days after the last streptozotocin injection. The metabolic parameters described above were measured weekly and (ipGTT) were performed at both endpoints. Moreover, to evaluate immune profiles, T cell and myeloid cell popula- tions were analysed by FACS in blood, spleen and pancreatic draining lymph nodes (pLN) of mice sacrificed at day 14.Results: Under physiological conditions lack of NIK didn’t affect β-cell development nor function. However, after MLDSTZ treatment, a signif- icantly higher diabetes incidence in NIKβKO mice was observed (83% NIKβKO mice vs 40% WT, n=15-17, p<0.05). Moreover, NIKβKO mice had markedly worse glucose control compared to WT during an IPGTT (492 mg/dL NIKβKO vs 400 mg/dL WT, p<0.05, 15 min). Furthermore, our preliminary results shows that NIKβKO mice display a discreet reduc- tion in the frequency of regulatory T cells (Tregs) (CD4+Foxp3+, 12.5%±5.6% NIKβKO vs 14.6%±4.8% WT) but noticeable higher frequencies of cytotoxic CD8+IFN-γ+ lymphocytes (55.0%±23.8% NIKβKO vs 38.2%±18.9% WT) in the pLN. Particularly, NIKβKO mice presented higher cytotoxic/Treg ratio (9.2±9.2 NIKβKO vs 3.8±4.0 WT) indicating local immune dysregulation in KO β-cells. Overall, the data suggest stronger inflammatory responses in β-cells that are KO for NIK, indicating a protective role for NIK in T1D.Conclusion: Our new results unveiled NIK as a new player on the crosstalk between β-cells and the immune cells leading to T1D. Revealing the downstream players of these network may allow new targeted approaches to treat or prevent T1D development.Supported by: Excellence of Science Grant – FNRS/FWODisclosure: P. Xiao: Grants; Excellence of Science Grant (EOS) Fonds National de Recherche Scientifique.