Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease resulting in pancreatic ?-cell destruction. It is hypothesized that viral infections can trigger T1D progression by direct lysis of ? -cells and/or the induction of an exacerbated pro-inflammatory milieu consisting of reactive oxygen species (ROS), cytokines, and islet- infiltrating leukocytes. We recently demonstrated the importance of NADPH oxidase (NOX)-derived ROS synthesis on autoimmune diabetes, as Non-Obese Diabetic (NOD) mice unable to generate superoxide (NOD.Ncf1m1J) were highly resistant to spontaneous T1D. The resistance was partly mediated by dampened innate immune responses, as superoxide-deficient macrophages induced diminished levels of pro- inflammatory cytokines and Type I interferons upon Toll-like receptor 3 (TLR3) stimulation. The goal of this project will mechanistically define the role of ROS synthesis on macrophage differentiation and anti-viral responses in murine macrophages and human monocytes. We hypothesize that NOX-derived ROS synthesis is necessary for efficient pro-inflammatory M1 macrophage development/differentiation and viral-induced Type 1 diabetes. To address this hypothesis, the following independent and interrelated aims will be defined. (1) Determine the effects of superoxide on M1 and M2 macrophage development and function. (2) Establish the contribution of redox-dependent signals to anti-viral responses in macrophages. (3) Define the role of superoxide synthesis on bystander activation in response to viral infections. Collectively, these studies will define the fundamental roles of NOX-derived superoxide in macrophage development/differentiation in T1D and the regulation of innate immune responses to diabetogenic viruses. The knowledge gained from these studies may influence the novel design of therapeutic strategies for T1D prevention.

Public Health Relevance

Our research has characterized the importance of reactive oxygen species (ROS) synthesis and oxidative stress on innate immune responses in Type 1 diabetes. Dissipation of ROS synthesis can prevent and delay T cell-mediated autoimmune destruction of pancreatic ?-cells. Our proposed studies will expand our knowledge of how pro-inflammatory innate immune signals synergize and influence autoreactive T cell responses in Type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099550-01A1
Application #
8761904
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2014-08-15
Project End
2019-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$319,725
Indirect Cost
$102,225
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294