Titre
Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice.
Type
article
Institution
Externe
Périodique
Auteur(s)
Yagishita, Y.
Auteure/Auteur
Uruno, A.
Auteure/Auteur
Chartoumpekis, D.V.
Auteure/Auteur
Kensler, T.W.
Auteure/Auteur
Yamamoto, M.
Auteure/Auteur
Liens vers les personnes
ISSN
1479-6805
Statut éditorial
Publié
Date de publication
2019-03
Volume
240
Numéro
3
Première page
403
Dernière page/numéro d’article
416
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. Although activation of Nrf2 signaling is known to exert anti-inflammatory effects, the function of Nrf2 in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, which are a polygenic model of human type 1 diabetes, to generate a genetic model for assessment of the contribution of Nrf2 activation to prevention and/or treatment of type 1 diabetes. Because Keap1 (Kelch-like ECH-associated protein 1) negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout Keap1 alleles, which enhanced Nrf2 signaling to moderate or excess levels, respectively. Nrf2 activation in the NOD::Keap1 FA/- mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion and prevented the development of diabetes mellitus. Notably, Nrf2 activation decreased both the plasma interferon-γ (IFN-γ) levels and the IFN-γ-positive cell numbers in the pancreatic islets. The amelioration of diabetes was also observed in the NOD mice with two hypomorphic Keap1 alleles (Keap1FA/FA) by intermediate activation of Nrf2. Both NOD::Keap1FA/- and NOD::Keap1FA/FA mice had a decreased incidence of diabetes mellitus, demonstrating that activation of Nrf2 signaling prevented the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for the prevention and treatment of type 1 diabetes.
PID Serval
serval:BIB_06EF9288E390
PMID
Open Access
Oui
Date de création
2023-09-03T18:34:49.292Z
Date de création dans IRIS
2025-07-09T18:23:31Z