On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic beta-cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The non-obese diabetic (NOD) mouse develops T1D spontaneously and serves as an animal model for human T1D. The heteroreceptor (HR), comprising IL-4Rα and IL-13Rα1, serves both IL-4 and IL-13 cytokines which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e. physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R−/−) display resistance to T1D as the rise in blood glucose level (BGL) and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+ ) mice. In fact, the frequency and spleen- to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R−/− mice. This is likely due to an increase in the frequency of mTGFβ+FoxP3int Tregs and persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.

Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets

“…31,32 Conversely, inhibiting the IL-4/IL-13 pathway via genetic deficiency of IL-4Ra or the IL-4Ra/IL-13Ra1 heteroreceptor is effective in controlling the blood glucose levels and islet inflammation. 33,34 The proposed mechanism suggests that IL-4Ra/IL-13Ra1 receptor deficiency increases the frequency of mTGFb + Foxp3 int Tregs and the persistence of CD206 + macrophages in the pancreas. 33 These results seem to fuel a debate about the controversial functions of these cytokines in the control of diabetogenic responses.…”

“…33,34 The proposed mechanism suggests that IL-4Ra/IL-13Ra1 receptor deficiency increases the frequency of mTGFb + Foxp3 int Tregs and the persistence of CD206 + macrophages in the pancreas. 33 These results seem to fuel a debate about the controversial functions of these cytokines in the control of diabetogenic responses. IL-4 and IL-13 are examples of cytokines that can target the same part of a receptor and perform overlapping functions; thus, blocking the affected receptors may produce multiple effects on the inflammatory process, which are not completely clarified.…”

Genetic Aspects of type 1 diabetes

“…IL-4 and IL-13 function to modulate autoimmunity. Furthermore, the IL-4/IL-13 pathway contributes to maintenance of peripheral tolerance and restrains development of T1DM [46]. PTPN2 is highly expressed in immune-related cells and its expression is modified in CD4+ T cells and more than 10 genetic regions in PTPN2 that demonstrate susceptibility to T1DM have been identified [47].…”

A distinct dendritic cell population arises in the thymus of IL-13Rα1-sufficient but not IL-13Rα1-deficient mice

“…We have previously demonstrated that the IL-4Rα/IL-13Rα1 heteroreceptor (HR) contributes to the development and function of APCs including macrophages [4, 12] and neonatal DCs as well as basophils[13]. Herein, comparative analysis was performed in HR +/+ and HR −/− mice to determine whether the HR plays a role in populating the thymus with functional APCs.…”