Dioxygenase TET2 mediated IL-6 repression contributes to β cell survival in NOD mice

Background Recently, we reported a novel β cell population with compromised β cell signatures that are able to survive and proliferate as a result of autoimmunity during the disease progression in NOD mice. The intrinsic vulnerability of β cells to ER stress and oxidative stress-induced dysfunction was noted in previous reports, in this study we are interrogating the possible role of the novel β cells in feeding the intra-islet inflammation through IL-6 amplifier, which leads to chemokines production, immune cells accumulation and β cells destruction.

Methods RNA-seq was performed to profile the difference between the normal and novel β cells. NOD mice was followed and analyzed for Tet methylcytosine dioxygenase 2 (Tet2) induction in β cells during the disease progression. Mouse and human islets were analyzed in vitro culture for IL-6 induction in β cells. Tet2 deficient mice were used to study the Tet2-IL6 axis in β cells.

Results Our RNA-seq data from NOD mice show that the novel β cells produce significantly more chemokines than the normal β cells. Tet2 can be induced in both human and mice islets culture with cytokines as well as in NOD mice during disease progression, in which Tet2 is consistently higher in normal β than the novel β cells. Cytokines present in the inflamed islets can synergistically induce IL-6 production in β cells, the level of which is even higher when Tet2 itself or Tet2 activity is absent in either mice or human islets.

In summary, we postulated that Tet2 can target IL-6 and tame the inflammation in β cells. The lack of Tet2-IL6 regulation in the novel β cells might account for high IL-6 production that feed-forward through the inflammation amplifier that accumulates immune cells and destruct real β cells.