Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults
biorxiv(2023)
Abstract
Aims/hypothesis Type 1 diabetes is characterised by pancreatic islet inflammation and autoimmune-driven pancreatic beta cell destruction. Type I interferons, such as IFNα, 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-1β). 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 IFNα and other proinflammatory cytokines (i.e. IFNγ and IL-1β).
Methods Inflammation, 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- βH1 cell line.
Results Pre-treatment with deucravacitinib prevented IFNα 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 IFNα- but not IFNγ-induced signalling pathway. Pre-treatment with deucravacitinib protected beta cells from the pro-apoptotic and proinflammatory effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially revert apoptosis and inflammation in cells previously treated with IFNα + IL-1β or IFNγ + IL-1β.
Conclusions/interpretation Our 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.
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### Competing Interest Statement
The authors have declared no competing interest.
* ATF3
: Activating transcription factor 3
CHOP
: C/EBP homologous protein
CXCL10
: C-X-C motif chemokine ligand 10
ER
: Endoplasmic reticulum
GAS
: Gamma-interferon activation site
ISG
: IFN-stimulated genes
ISRE
: IFN-stimulated regulatory element
JAK
: Janus kinase
MX1
: MX Dynamin Like GTPase 1
PKR
: Double-stranded RNA sensor protein kinase R
Poly(I:C)
: Polyinosinic-polycytidylic acid
STAT
: Signal transducer and activator of transcription
TYK2
: Tyrosine kinase 2
XBP1
: X-box binding protein 1
XBP1s
: Spliced isoform of XBP1
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