Type 2 Diabetes Mellitus is a chronic weakening disease involving about 400 million people worldwide, in particular in the civilized countries. It is associated with many chronic complications, both macrovascular and microvascular: nephropathy, retinopathy, cardio-vascular disease and erectile dysfunction. In particular, one important long-term complication involved the vascular district and, together with diabetic neuropathy, leads to permanent nerve damage and augmented risk of diabetic ulcers or wounds in legs and foot. One process that controls vascular regeneration is angiogenesis, that is reported to be dysregulated in type 2 diabetes. Indeed, new vessels formation in diabetes is augmented on the retina and reduced in peripheral limbs, in particular in foot lesions.
S100B is a low molecular weight protein expressed in several cell types, of both neural and vascular origin. It exerts both intracellular and extracellular effects, that are mediated by its interaction with RAGE transmembrane receptor. S100B can regulate different steps of the angiogenic process, in particular cell proliferation and migration, but these effects are not fully explained. The first chapter of the thesis aims to investigate in vitro and in vivo the role of the protein in different steps of the angiogenic process, and to verify the relevance of S100B-RAGE ligation and the involvement of ERK1/2 Kinase pathway.
A good immune system is also necessary to prevent infections on diabetic foot. Blood myeloid cell population is actively involved in defensive mechanisms by the recruitment of circulating monocytes and their interaction with endothelial cells. Dendritic cells instead are essential to process and present the antigen to lymphocytes, promoting the immune response.
A recurrent marker expressed on almost all myeloid cells at different degree of intensity is CD33, that is considered a marker of immunity but its role is still unclear. CD33 contains ITIM inhibitory motifs that can control the inflammatory response, preventing cytokine signalling and monocytes activation, but there are no informations about the connection with the diabetic disease.
The second chapter of the thesis aims to evaluate the presence of CD33 on peripheral blood cells in type 2 diabetic patients with or without complications and to mimic the in vivo hyperglycemic environment on cultured mononuclear cell to assess the behavior of CD33 in monocytes and dendritic cells in healthy controls and diabetic patients with foot lesions
