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bioRxiv · 10.1101/2022.12.27.522037

Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults

Dos Santos, R. S.·Guzman-Llorens, D.·Perez-Serna, A. A.·Nadal, A.·Marroqui, L.
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Abstract

Aims/hypothesisType 1 diabetes is characterised by pancreatic islet inflammation and autoimmune-driven pancreatic beta cell destruction. Type I interferons, such as IFN, are key players in early human type 1 diabetes pathogenesis, as the activation of the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway induces inflammation, a long-lasting MHC class I overexpression, endoplasmic reticulum (ER) stress, and beta cell apoptosis (in synergy with IL-1{beta}). As TYK2 inhibition has been suggested as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect beta cells against the damaging effects of IFN and other proinflammatory cytokines (i.e. IFN{gamma} and IL-1{beta}). MethodsInflammation, ER stress, and apoptosis were evaluated by real-time PCR, immunoblot, immunofluorescence, and nuclear dyes. The promoter activity was assessed by luciferase assay and insulin secretion and content by ELISA. All experiments were performed in the human EndoC- {beta}H1 cell line. ResultsPre-treatment with deucravacitinib prevented IFN effects, such as STAT1 and STAT2 phosphorylation and protein expression as well as MHC class I hyperexpression, in a dose-dependent manner without affecting beta cell survival and function. Comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFN- but not IFN{gamma}-induced signalling pathway. Pre-treatment with deucravacitinib protected beta cells from the pro-apoptotic and proinflammatory effects of two different combinations of cytokines: IFN + IL-1{beta} and IFN{gamma} + IL-1{beta}. Moreover, this TYK2 inhibitor could partially revert apoptosis and inflammation in cells previously treated with IFN + IL-1{beta} or IFN{gamma} + IL-1{beta}. Conclusions/interpretationOur findings suggest that, by protecting beta cells against the deleterious effects of proinflammatory cytokines without affecting beta cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes. Research in contextWhat is already known about this subject? O_LIIn type 1 diabetes, pancreatic beta cells are killed by the immune system C_LIO_LIIn early insulitis, type I interferons are crucial for the dialogue between the immune system and pancreatic beta cells C_LIO_LIActivation of the TYK2-STAT pathway by IFN induces inflammation, HLA class I overexpression, ER stress, and beta cell apoptosis. C_LI What is the key question? O_LICould the TYK2 inhibitor deucravacitinib prevent the deleterious effects of IFN and other cytokines in beta cells? C_LI What are the new findings? O_LIDeucravacitinib prevented IFN effects in a dose-dependent manner without affecting beta cell function and survival C_LIO_LIPre-treatment with deucravacitinib protected beta cells against apoptosis and inflammation induced by two different combinations of cytokines: IFN + IL-1{beta} and IFN{gamma} + IL-1{beta} C_LIO_LIAddition of deucravacitinib to cells pre-treated with IFN + IL-1{beta} or IFN{gamma} + IL-1{beta} partially reverted apoptosis and inflammation induced by these cytokines C_LI How might this impact on clinical practice in the foreseeable future? O_LIDue to its protective effect against proinflammatory cytokines in beta cells, our findings suggest that deucravacitinib could be repurposed for the prevention or treatment of type 1 diabetes. C_LI

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Dos Santos, R. S., Guzman-Llorens, D., Perez-Serna, A. A., Nadal, A., Marroqui, L.. 2022-12-29. Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults. https://doi.org/10.1101/2022.12.27.522037

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