scholarly journals Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice

2019 ◽  
Vol 240 (3) ◽  
pp. 403-416 ◽  
Author(s):  
Yoko Yagishita ◽  
Akira Uruno ◽  
Dionysios V Chartoumpekis ◽  
Thomas W Kensler ◽  
Masayuki Yamamoto
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Critical Role ◽  
Nod Mice ◽  
Related Factor ◽  
Autoreactive T Cell ◽  
Nrf2 Activation ◽  
Ifn Γ

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.

scholarly journals MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis

2021 ◽  
Author(s):  
Tiantian Yue ◽  
Fei Sun ◽  
Faxi Wang ◽  
Chunliang Yang ◽  
Jiahui Luo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Adoptive Transfer ◽  
Nod Mice ◽  
Transcriptional Level ◽  
Clinical Settings ◽  
Cpg Dna ◽  
Ifn Γ

AbstractThe methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

scholarly journals IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes

Diabetologia ◽  
2010 ◽  
Vol 53 (7) ◽  
pp. 1451-1460 ◽  
Author(s):  
L. G. Petrich de Marquesini ◽  
J. Fu ◽  
K. J. Connor ◽  
A. J. Bishop ◽  
N. E. McLintock ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
First Degree Relatives ◽  
Ifn Γ ◽  
Islet Antigen

scholarly journals T-Cell–Specific PTPN2 Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune Comorbidities

Diabetes ◽  
2019 ◽  
Vol 68 (6) ◽  
pp. 1251-1266 ◽  
Author(s):  
Florian Wiede ◽  
Thomas C. Brodnicki ◽  
Pei Kee Goh ◽  
Yew A. Leong ◽  
Gareth W. Jones ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Nod Mice

scholarly journals Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Diabetes ◽  
2006 ◽  
Vol 55 (7) ◽  
pp. 2098-2105 ◽  
Author(s):  
P. Alard ◽  
J. N. Manirarora ◽  
S. A. Parnell ◽  
J. L. Hudkins ◽  
S. L. Clark ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
Nod Mice ◽  
Antigen Presenting Cell ◽  
Diabetes Development ◽  
Antigen Presenting

scholarly journals CD4+ T cell-dominant insulitis in acute-onset Type 1 diabetes mellitus associated with intraductal papillary mucinous adenoma

2016 ◽  
Vol 63 (9) ◽  
pp. 841-847
Author(s):  
Ken Yajima ◽  
Yoichi Oikawa ◽  
Kentaro Ogata ◽  
Akinori Hashiguchi ◽  
Akira Shimada
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Type 1 Diabetes Mellitus ◽  
Acute Onset ◽  
Onset Type

scholarly journals A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice

Diabetes ◽  
2002 ◽  
Vol 51 (2) ◽  
pp. 339-346 ◽  
Author(s):  
W. Gurr ◽  
R. Yavari ◽  
L. Wen ◽  
M. Shaw ◽  
C. Mora ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Nod Mice ◽  
Onset Type ◽  
Family Protein ◽  
New Onset

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

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