Redox-Sensitive Innate Immune Pathways During Macrophage Activation in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease resulting in β-cell destruction mediated by islet-infiltrating leukocytes. The role of oxidative stress in human and murine models of T1D is highly significant as these noxious molecules contribute to diabetic complications and β-cell lysis, but their direct impact on dysregulated autoimmune responses is highly understudied. Pro-inflammatory macrophages play a vital role in the initiation and effector phases of T1D by producing free radicals and pro-inflammatory cytokines to facilitate β-cell destruction and to present antigen to autoreactive T cells. Recent Advances: Redox modulation of macrophage functions may play critical roles in autoimmunity. These include enhancing pro-inflammatory innate immune signaling pathways in response to environmental triggers, enforcing an M1 macrophage differentiation program, controlling antigen processing, and altering peptide recognition by oxidative post-translational modification. Therefore, an oxidative environment may act on multiple macrophage functions to orchestrate T1D pathogenesis.

Mechanisms involved in the initiation of T1D remain unclear, making preventive and early therapeutics difficult to develop. Although many of these advances in the redox regulation of macrophages are in their infancy, they provide insight into how oxidative stress aids in the precipitating event of autoimmune activation.

Future studies should be aimed at mechanistically determining which redox-regulated macrophage functions are pertinent in T1D pathogenesis, as well as at investigating potential targetable therapeutics to halt and/or dampen innate immune activation in T1D.