Characterisation of macrophage populations in the Non-Obese Diabetic (NOD) mouse - a preclinical model of type 1 diabetes

Sara Falcone, University of Oxford

 

Aims

Type 1 diabetes (T1D) is an autoimmune endocrine disease caused by the selective destruction of the insulin-producing β-cells of the islets of Langerhans by autoantigen-specific inflammatory T cells.

Along with autoreactive T cells, macrophages (Mφs), in particular pro-inflammatory classically activated macrophages (CAMφs), are the first cells that infiltrate the islets of Langerhans leading to the production of reactive oxygen species (ROS) and proinflammatory cytokines, creating a cytotoxic environment for the β-cells.

Several publications report that in non-obese diabetic (NOD) mouse, the T1D preclinical model closest to man, islet Mφs demonstrate alterations in metabolism (e.g., upregulation of genes linked with oxidative phosphorylation and ROS response) and an increased inflammatory signature.

Using bone marrow derived macrophages (BMDMs) and assays such as the Seahorse extracellular flux analysis platform, we were able to recapitulate the phenotype ex vivo, observing a significant alteration in NOD Mφs metabolism in comparison to C57BL/6 (a diabetic resistant strain).

In order to deepen the investigation, I aim to undertake unbiased proteomics to identify the molecular pathways driving these differences.

 

Grant awarded: £5,000