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Unveiling the role of NF-κB-inducing kinase (NIK) and receptor-interacting protein kinase 1 (RIPK1) in diabetes development

par Xiao, Peng
Président du jury Le Moine, Alain
Promoteur Cardozo, Alessandra K
Co-Promoteur Gurzov, Esteban Nicolas
Publication Non publié, 2023-01-17

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Résumé :

Type 1 diabetes (T1D) is caused by progressive destruction of insulin-producing β-cells by autoreactive immune cells. Type 2 diabetes (T2D) is characterized by chronic inflammation, insulin resistance in peripheral insulin-responsive organs and β-cell failure. β-cell dysfunction and death are characteristic of both T1D and T2D; however, the mechanisms associated with β-cell death in diabetes remain to be clarified. Pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF) and CD40L, secreted by immune cells during islet inflammation in diabetes, induce the activation of inflammatory and death-related pathways within β cells, such as tumor necrosis factor receptor 1 (TNFR1) signaling and the downstream transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB signaling occurs through two main pathways, a canonical pathway that has been shown to contribute to β-cell death in T1D, and a non-canonical pathway that has not been extensively studied in T1D. As one of the important molecules involved in TNFR1 signaling, the protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1), promotes inflammation by acting as a scaffold for NF-κB and MAPK activation, or as a kinase that triggers apoptosis and/or necroptosis. However, its role in diabetes, especially of its kinase activity, is not yet elucidated.We have previously found in vitro that proinflammatory cytokine treatment, which induces β-cell death, promotes stabilization of NF-κB-inducing kinase (NIK) and activation of downstream NF-κB signaling in rat β-cells. Moreover, recent studies that specifically overexpressed NIK in β-cells showed conflicting results, i.e., mice directly overexpressing NIK in β-cells developed spontaneous immune-mediated diabetes due to severe insulitis, whereas mice indirectly overexpressing NIK did not show abnormal glucose metabolism under physiological conditions. Therefore, in Study I, we constructed two lines of β-cell-specific knockout NIK mice (NIKβKO and Ins1CreNIKKO), to evaluate the role of endogenous NIK on diabetes and obesity. β-cell specific NIK KO mice under physiological conditions develop normally and exhibit normal glucose metabolism characteristics. When inducing immune-mediated diabetes in these mice, we found that NIK deletion had no effect on β-cell survival, pro-inflammatory responses, and diabetes development. Moreover, we also showed that β-cell NIK expression had no effect in obesity-induced metabolic disorders.In Study II, we investigated whether the absence of RIPK1 kinase activation affects susceptibility to immune-mediated diabetes or diet induced obesity (DIO). We showed that knock-in mice carrying a mutation mimicking phosphorylation on Ser25 by IKKs (Ripk1S25D/S25D) that abrogates RIPK1 kinase activity, presented normal glucose metabolism and β-cell function under physiological conditions. Furthermore, immune-mediated diabetes and DIO did not differ between Ripk1S25D/S25D and wildtype littermates. Our in vitro findings suggested that RIPK1 kinase can be activated in human β-cells and its downstream necroptotic components were phosphorylated, but no RIPK kinase-mediated cell death was observed in either human β-cells or murine islets. Our results suggest that the regulation of the RIPK kinase activity on cell death is cell type-specific and that β-cells are resistant to it.Overall, our study revealed that NIK expression in β-cells do not contribute to the development of diabetes. Moreover, β-cells, contrary to other cell types, are resistant to RIPK1 kinase-dependent cell death and RIPK1 is not involved in the development of immune-mediated β-cell death and DIO.