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The role of NF-kappa B-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 57th EASD Annual Meeting of the European Association for the Study of Diabete, Diabetologia, Diabetologia (64 (Suppl 1):S1–S380)
Publication Publié, 2021-09-01

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Résumé :

Background and aims: In type 1diabetes (T1D) β-cell destruction results from an aberrant inflammatory crosstalk between β-cells and immune cells partly mediated via activation of the transcription factor NF-κB. NF-κB signaling occurs through two major pathways, the canonical, which was shown to contribute to β-cell death in T1D, and the alternative, which has not been extensively studied in T1D. The alternative pathway is characterized by the stabilization of NF-κB-inducing kinase (NIK) triggering p100 processing into p52, which dimerizes with RelB to regu- late gene transcription. Specific ligands activating the alternative pathway are present in the serum of T1D patients and contribute to autoimmunity in non-obese diabetic mice. In vitro, pro-apoptotic cytokine treatment, promotes NIK stabilization and activation of downstream NF-κB signal- ing in β-cells. A recent study revealed that β cell-specific overexpression of NIK results in spontaneous diabetes in mice due to β cell death and insulitis, however physiological NIK expression is extremely low and thus overexpression of NIK is not an ideal study model. The aim of our study was to evaluate the role of NIK in β-cell demise during T1D in models where physiologic levels of this protein were expressed.Materials and methods: A β-cell specific NIK KO mouse (NIKβKO) was generated to verify the in vivo role of NIK in β-cells in physiological condition and in T1D induced by multiple low-dose of streptozotocin (MLDSTZ). Weekly glycemia and bodyweight were monitored. IpGTT, β-cell/islet mass and pancreas insulin content were performed. Moreover, immune profiles of T cell and myeloid cell populations were evaluated in blood, spleen and pancreatic draining lymph nodes (pLN). In vitro, β-cell death, GSIS and gene expression were analyzed in mouse islets, EndoC-βH1 cells and/or human β-cells exposed to proinflammatory cyto- kines (IL-1β+IFN-γ) and/or to ligands of the alternative NF-κB pathway (LIGHT and LTβR agonist).Results: In physiological conditions lack of NIK did not affect β-cell development or function. Moreover, after MLDSTZ treatment, metabolic parameters including glycemia, ipGTT, and recruitment of Foxp3+Treg, CD8+IFN-γ+ and CD4+IFN-γ+ T cells in blood, pLN and spleen were indistinguishable between NIKβKO and WT mice. β-cell mass and islet density were also not different between NIKβKO and WT mice. These results suggest that lack of NIK does not affect insulitis or β-cell demise in our model. Furthermore, cytokines and specific ligands of the alternative NF-κB pathway did not affect β-cell death and insulin secretory function (GSIS) in mouse islets or human β-cells. NIK mediated NF-κB induction in human β-cells did not regulate downstream proinflammatory gene transcription such as Fas, Cxcl1 and Ccl2.Conclusion: Overall, our data suggests that ablation of NIK has no major effects in β-cells both in vitro and in vivo. Therefore, we postulate that NIK and the alternative NF-κB pathway do not play a significant role in β-cell insulitis and diabetes development.Supported by: Excellence of Science Grant (FNRS, Belgium, convention 30826052)Disclosure: P. Xiao: None.