Molecular programs involved in balance of SOCS-1/MyD88 expression in macrophages from individuals with diabetes and consequences in response to infection

Abstract

According to the World Health Foundation (1999), diabetes mellitus describes a metabolic disorder characterized by chronic hyperglycemia with metabolism disturbances. Type 1 diabetes (T1D) is developed by immunologic Beta-pancreatic cell destruction leading to deficient insulin production. It is established that diabetic patients develop a variety of associated morbidities like retinopathy, wound healing dysfunctions, atherosclerosis and increased infection susceptibility but the exact contribution of hyperglycemia and insulin deficiency is not known. Recently we described that alveolar macrophages from diabetic rats present imbalance on SOCS-1/MyD88 expression. Since MyD88 has a central role on macrophages response against pathogens, the molecular mechanisms involved in the regulation of its expression on macrophages from diabetics is a subject of interest. Even though the role of SOCS-1 on macrophages/phagocytes MyD88-dependent response had been already described, the molecular mechanisms involved on SOCS-1 and MyD88 expression regulation in TD1 still remain to be determined. Moreover, it is not known how SOCS-1/MyD88 expression on macrophages affects bacterial susceptibility on T1D. Thus, our aim is to study the molecular programs involved on SOCS-1 and MyD88 expression in macrophages from diabetic animals and the outcome on infection susceptibility. Initially, it will be determined the effect of hyperglycemia vs. insulin on macrophages SOCS-1/MyD88 balance and how it affects TLRs-dependent macrophages response. Using macrophages from chemically (streptozotocin) and genetically (NOD mice) induced diabetic mice, the profile of inflammatory microRNA expression and its ability to modulate SOCS-1/MyD88 expression will be analyzed. Then, selected microRNAs will be silenced and TLRs agonists response will be evaluated in macrophages. In addition, macrophage's microRNA profile expression from diabetic animals during infection and how the selected microRNAs contribute to macrophage's response will be assessed. Finally, using a mouse model that have SOCS-1 deficient myeloid cells, the inflammatory response and survival in different infection models will be evaluated. Unveiling molecular programs involved on macrophages SOCS-1/MyD88 expression and its outcome in infection can help identifying new therapeutic targets to improve life quality of diabetic patients. (AU)