Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes

Abstract

Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

Redox Regulation of m6A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes

“…We chose to infuse PBS or AAV8 into 4-week-old animals (Figure 6B) because our data showed that Mettl3 levels start to decline after this age in NOD females (Figure 1A and 1H). We confirmed Mettl3 protein overexpression at 12 weeks of age (Figure 6C) and followed these mice for up to 25 weeks of age similar to previous studies in the NOD mouse model (Kulkarni et al, 2021; Nelson et al, 2020; Rui et al, 2021). Body weight trajectories didn’t change until 17 weeks of age when mice that received AAV8 driving eGFP overexpression (AAV8-eGFP) or PBS started to lose weight compared to mice that received AAV8 driving Mettl3 overexpression (AAV8-Mettl3) (Figure 6D).…”

Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes

“…Studies in NOD mice have been supportive of the notion that autonomous characteristics of β cells might allow for their evasion from immune attack ( Fenske et al, 2017 ; Lee et al, 2020 ; Rui et al, 2017 ; Thompson et al, 2019 ). Recently, inflammatory signaling by Tet2 within β cells has been proposed as a modifier of the immune response in NOD mice ( Rui et al, 2021 ). Because Tet2 is expressed in a host of immune cells, the definitive role of inflammatory signaling within β cells and its mechanism in mediating cellular crosstalk, however, remains to be elucidated.…”

Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes

“…Of these, the former is characterized by the progressive destruction of pancreatic β cells, while the latter is characterized by peripheral insulin resistance. Although the pathogenesis of DM has been extensively studied, − its treatment still focuses on glycemic control. Therefore, it is of great significance to develop new treatment strategies to solve this major public health problem.…”