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Diabetes. 2015 Feb;64(2):604-17. doi: 10.2337/db14-0803. Epub 2014 Sep 3.

Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.

Author information

1
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA lindayip@stanford.edu.
2
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA.
3
Department of Medicine, Columbia Center for Translational Immunology and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY.
4
Type 1 Diabetes Center, The La Jolla Institute for Allergy and Immunology, La Jolla, CA.

Abstract

Peripheral tolerance is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs). We previously identified a transcriptional regulator, deformed epidermal autoregulatory factor 1 (Deaf1), that can regulate PTA expression in LNSCs of the pancreatic lymph nodes (PLNs). During the pathogenesis of type 1 diabetes (T1D), Deaf1 is spliced to form the dominant-negative isoform Deaf1-Var1. Here we show that Deaf1-Var1 expression correlates with the severity of disease in NOD mice and is reduced in the PLNs of mice that do not develop hyperglycemia. Inflammation and hyperglycemia independently drive Deaf1 splicing through activation of the splicing factors Srsf10 and Ptbp2, respectively. Inflammation induced by injection of activated splenocytes increased Deaf1-Var1 and Srsf10, but not Ptbp2, in the PLNs of NOD.SCID mice. Hyperglycemia induced by treatment with the insulin receptor agonist S961 increased Deaf1-Var1 and Ptbp2, but not Srsf10, in the PLNs of NOD.B10 and NOD mice. Overexpression of PTBP2 and/or SRSF10 also increased human DEAF1-VAR1 and reduced PTA expression in HEK293T cells. These data suggest that during the progression of T1D, inflammation and hyperglycemia mediate the splicing of DEAF1 and loss of PTA expression in LNSCs by regulating the expression of SRSF10 and PTBP2.

PMID:
25187368
PMCID:
PMC4303971
DOI:
10.2337/db14-0803
[Indexed for MEDLINE]
Free PMC Article

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