The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis

Abstract

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of insulin-secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β-cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4(+) and CD8(+) T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β-cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β-cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox-dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β-cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL-1 and IFN-γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.

Figure 1

ROS-derived proinflammatory cytokines provide a third signal for optimal effector responses of naive CD8⁺ T cells. Cross-presentation of β-cell antigens to naive CD8⁺ T cells in the presence of ROS and proinflammatory cytokines IL-12 and IFN-α/β will facilitate the maturation of CTLs. Pancreatic β cells will be destroyed by CTLs by FasL (CD95), which upon binding to Fas expressed on the surface of β cells induces death, in addition to secretion of granzyme and perforin and the proinflammatory cytokines TNF-α, IFN-γ, and IL-1β.

Figure 2

ROS-derived proinflammatory cytokines provide a third signal for optimal effector responses of naive CD4⁺ T cells. Naive CD4⁺ T cells mature into potent effectors of β cell destruction when stimulated with processed pancreatic β-cell epitopes presented on MHC II molecules, costimulatory molecules, and soluble mediators such as ROS, IL-1, and TNF-α. Activated effector CD4⁺ T cells will secrete the pleiotropic proinflammatory cytokine TNF-α, in addition to IFN-γ, to directly destroy β cells and/or facilitate the recruitment and activation of accessory cells, such as macrophages, NK cells, or CTLs, to mediate pancreatic β-cell destruction.

Figure 3

Nitric oxide mediates the inhibitory actions of cytokines on insulin secretion. Cytokines (IL-1 and IFN-γ) stimulate iNOS expression and the production of micromolar levels of nitric oxide in β cells. Nitric oxide inhibits the oxidation of glucose to CO₂, resulting in the attenuation of glucose-dependent ATP generation. The net effect is an inhibition in the closure of ATP-sensitive potassium channels, preventing β-cell depolarization, calcium influx, and calcium-dependent insulin exocytosis.

Figure 4

Transcriptional regulation by FOXO1 and Sirt1 in response to nitric oxide. Nitric oxide stimulates FOXO1 nuclear localization. When Sirt1 is more active, FOXO1 is deacetylated and directs the expression of protective factors such as the DNA repair gene GADD45α. When Sirt1 is less active, FOXO1 is acetylated (FOXO1-AC) and directs the expression of proapoptotic factors such as PUMA.

Figure 5

The pathways controlling the β-cell response to cytokines. Cytokines (IL-1 and IFN-γ) stimulate iNOS expression and the production of micromolar levels of nitric oxide in β cells. Nitric oxide stimulates the nuclear localization of FOXO1 that is associated with the loss of the AKT-mediated inhibitory phosphorylation. In the nucleus, FOXO1 directs a transcriptional program, as described in the legend to Figure 2. Mechanisms responsible for the regulation of Sirt1 activity are unknown, but irreversible DNA damage is associated with a commitment of β cells to death in response to cytokines. Decreased cellular levels of NAD⁺, associated with impaired mitochondrial oxidative capacity, may contribute to the regulation of this NAD⁺-dependent deacetylase. Overactivation of poly ADP-ribose polymerase (PARP) following extensive DNA damage is one potential mechanism of NAD⁺ depletion; however, we have shown that cytokines do not overactivate PARP-1 in islets.