Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets

Abstract

Alarming rates of diabetes mellitus (DM) demonstrated that this disease has become a major problem in public health field worldwide. Currently, there are about six million of diabetic patients in Brazil. The etiology of diabetes remains unclear, but it is known that the risk of developing the disease is determined by genetic factors and the interference of environmental factors including viral infections, food, toxins, stress and intestinal microbiota. T1D is characterized by pancreas dysfunction resulting from autoimmune selective destruction of the insulin-producing ² cells of the islets of Langerhans by autoreactive T lymphocytes. In contrast, the T2D is a systemic autoinflammatory disorder associated with obesity, triggered by the activation of innate immunity cells that leads to insulin resistance. Despite these differences, the inflammatory response drived to self-constituents represents a common denominator in the development of both DM1 and DM2. More recently it was discovered that endogenous markers called damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are recognized by receptors cytosolic NLR (NOD-like receptors) resulting in several proinflammatory cytokine production. In spite of inflammation represents a central axis in the DM development, only few experimental studies have evaluated the functional role of NLR receptors in T1D and T2D pathogenesis. Initially, we intend to evaluate the role of NLRP1 NLRP3 receptors in inflammatory response and adaptive immunity polarization mediated by lymphocytes in T1D. In parallel, we aim to investigate the importance of receptors NOD1 and NOD2 in innate immunity modulation dependent on intestinal microbiota alterations in T2D. Considering the high incidence of DM, particularly its complications, it is important to search for new knowledge about the pathogenesis of these diseases. Therefore, our aim is to evaluate the involvement of NLRs receptors and their signaling pathways during the T1D and T2D onset. It is important to mention that the identification of new molecular targets could be used in the formulation and implementation of therapeutic strategies against these diseases, but also improve the quality of life by minimizing the progression of the diabetic complications. (AU)