Interplay between macrophage polarization, glucose metabolism and oxidative stress

Abstract

Macrophages have a wide variety of locations and functions that are determined by its origin and the type of activation imposed by the environment. Under an academic point of view macrophage activation can be classified as pro-inflammatory (M1 polarization), anti-inflammatory (M2) or pro-resolution/deactivation (M0), these profiles coexisting in the course of the immune response, and play a relevant functional role in the onset of inflammation. Our group has focused its work on studying the role of macrophages in the pathophysiology of major organs. A line of interest has been the characterization of signaling pathways that determine the polarization and its effect on the release of mediators of inflammation. In addition to this, these mediators affect the function and gene expression in differentiated cells, such as hepatocytes, cardiomyocytes and myofibroblasts. We recently analyzed the metabolic aspects associated with macrophage activation trying to answer the question about what changes in the regulation of energy metabolism and precursors (NADPH, riboses, etc..) accompany the different types of polarization and to what extent these changes are necessary for the activation phenotype. To get an idea of the magnitude of changes involved, for example after M1 activation through TL4 challenge, there is an alteration in the expression of over a thousand of genes. The interest of these studies is to envisage the possibility to regulate macrophage function by altering their metabolic activity as a complementary strategy to regulate their participation in the inflammatory response. We could show that regardless of the stimulus used and the availability of energy substrates, the macrophage is in more than 90% glycolytic, with limited use of other fuels for energy purposes; however, the pathways to generate metabolites from the TCA and glutaminolysis are fully functional and these molecules are used for other purposes. In this context, we have investigated the role of macrophages in the development of atherogenesis, its diagnosis and its contribution to plaque stability and culprit and non-culprit acute coronary events. Indeed, this response has been also evaluated in the context of the infiltration in the heart under pathophysiological situations. Following an ischemic process or in the course of infectious myocarditis the heart elicits an inflammatory response that promotes the infiltration and activation of resident and circulating inflammatory cells, representing up to 4-5% of the heart population. The analysis of the infiltration in prototypical situations such as post-myocardial ischemia and myocarditis (through activation of TLRs or models of autoimmune myocarditis) allows the examination of the nature of the process of macrophage activation in the heart and might help to unravel the role of the recruitment of inflammatory cells to the establishment of the cardiac dysfunction and the contribution of the metabolic profile, including the oxidative stress to this pathological situation.