Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolism.

Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the “all or none” pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources.

Alzheimer's disease (AD) is a neurodegenerative disorder in which oxidative stress has been implicated as an important event in the progression of the pathology. In particular, it has been shown that protein modification by reactive oxygen species (ROS) occurs to a greater extent in AD than in control brain, suggesting a possible role for oxidation‐related decrease in protein function in the process of neurodegeneration. Oxidative damage to proteins, assessed by measuring the protein carbonyl content, is involved in several events such as loss in specific protein function, abnormal protein clearance, depletion of the cellular redox‐balance and interference with the cell cycle, and, ultimately, neuronal death. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. Previously, we used our proteomics approach, which successfully substitutes for labor‐intensive immunochemical analysis, to detect proteins and identified creatine kinase, glutamine synthase and ubiquitin carboxy‐terminal hydrolase L−1 as specifically oxidized proteins in AD brain. In this report we again applied our proteomics approach to identify new targets of protein oxidation in AD inferior parietal lobe (IPL). The dihydropyrimidinase related protein 2 (DRP‐2), which is involved in the axonal growth and guidance, showed significantly increased level in protein carbonyls in AD brain, suggesting a role for impaired mechanism of neural network formation in AD. Additionally, the cytosolic enzyme α‐enolase was identified as a target of protein oxidation and is involved the glycolytic pathway in the pathological events of AD. Finally, the heat shock cognate 71 (HSC‐71) revealed increased, but not significant, oxidation in AD brain. These results are discussed with reference to potential involvement of these oxidatively modified proteins in neurodegeneration in AD brain.