Downregulation of the circadian rhythm related gene Arntl2 suppresses diabetes protection in Idd6 NOD.C3H congenic mice

Abstract

1. Our previous studies of the murine genetic locus Idd6 revealed the aryl hydrocarbon receptor nuclear translocator-like protein 2 (Arntl2) as a candidate gene for type 1 diabetes; and in Idd6 NOD.C3H congenic mice, Arntl2 upregulation is linked to decreased diabetes development. 2. In the present study, shRNA plasmids capable of suppressing Arntl2 expression were developed and given to diabetes resistant NOD.C3H congenic mice by hydrodynamic tail vein injection. The effects of Arntl2 suppression on diabetes incidence and immune cell numbers were investigated. 3. Diabetes incidence was increased by Arntl2 mRNA interference in the congenic strain and this was associated with an increase in CD4(+) T cells and a decrease in regulatory T cells in the peripheral immune system. 4. These results provide additional support for the protective role of the Arntl2 gene located in locus Idd6 in diabetes progression in NOD.C3H congenic mice.

Linking the Circadian Rhythm Gene Arntl2 to Interleukin 21 Expression in Type 1 Diabetes

“…Knowing the role of IL21 in the immune system, the expansion of T cells, and in particular as being a major factor in T1D (19)(20)(21)(22), our previous results become explainable (14,15). The decrease in diabetogenic activity of Arntl2-overexpressing splenocytes could be related to decreased IL21 production.…”

“…In addition, several polymorphism and different splice forms were identified when comparing the gene and its transcripts in C3H and NOD strains (10). Diabetes incidence is increased by Arntl2 mRNA interference in Idd6 congenic mice concomitant with an increase in CD4 + T cells and a decrease in regulatory CD4 + CD25 + T cells in the peripheral immune system (14). In addition, upregulation of cellular Arntl2 levels correlates with inhibited CD4 + T-cell proliferation and their decreased diabetogenic activity (15).…”

Use of Congenic Mouse Strains for Gene Identification in Type 1 Diabetes

“…We recently reported functional studies aimed at correlating Arntl2 expression to T cell activation and diabetes transfer. Our results show that upregulation of Arntl2 inhibits the proliferation rate of CD4 + T cells ex vivo and suppresses the disease promoting activity of diabetogenic splenocytes in vivo, whilst suppression of Arntl2 by RNAi leads to expansion of CD4 + T cells in vivo, to decreased levels of regulatory T cells and to increased diabetes incidence (He et al, 2010a(He et al, , 2010b. …”

Clock genes alterations and endocrine disorders

“…103 BMAL1 regulates also diurnal oscillations of Ly6C (hi) inflammatory monocytes 104 and CRY the expression of pro-inflammatory cytokines. 105 In particular, ARNTL2 gene has been discovered as a candidate gene for T1DM within the Idd6 locus of the nonobese diabetic mouse, 106,107 regulating proliferation of peripheral CD4 (+) T cells and thus diabetes development. 108,109 ARNTL2 binds to the promoter of the interleukin-21 (IL-21) gene, which itself controls the proliferation of immune cells and associated with human T1DM.…”