Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-βH1 β-cells against proinflammatory insults

Front Immunol. 2023 Oct 3:14:1263926. doi: 10.3389/fimmu.2023.1263926. eCollection 2023.

Abstract

Introduction: Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic β-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and β-cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect β-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1β).

Methods: All experiments were performed in the human EndoC-βH1 β-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay.

Results: Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting β-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected β-cells from the effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β.

Discussion: Our findings suggest that, by protecting β-cells against the deleterious effects of proinflammatory cytokines without affecting β-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

Keywords: TYK2; apoptosis; deucravacitinib; inflammation; pancreatic β-cells; type 1 diabetes; type I interferons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / pharmacology
  • Diabetes Mellitus, Type 1* / metabolism
  • Humans
  • Inflammation
  • Interferon-alpha / metabolism
  • TYK2 Kinase*

Substances

  • TYK2 Kinase
  • deucravacitinib
  • Cytokines
  • Interferon-alpha

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. LM is funded by the grant PID2020-117569RA-I00 by MCIN/AEI/10.13039/501100011033 and by the grant SEJI/2018/023 by Generalitat Valenciana. AN is supported by European Union’s Horizon 2020 research and innovation programme under grant agreement GOLIATH No. 825489, by the grant PID2020-117294RB-I00 by MCIN/AEI/10.13039/501100011033, and by the grant PROMETEO II/2020/006 by Generalitat Valenciana. This research was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red (CB07/08/0002), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación.