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.

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Nitration of tyrosine in biological conditions represents a pathological event that is associated with several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (AD). Increased levels of nitrated proteins have been reported in AD brain and CSF, demonstrating the potential involvement of reactive nitrogen species (RNS) in neurodegeneration associated with this disease. Reaction of NO with O À:2 leads to formation of peroxynitrite ONOO -, which following protonation, generates cytotoxic species that oxidize and nitrate proteins. Several findings suggest an important role of protein nitration in modulating the activity of key enzymes in neurodegenerative disorders, although extensive studies on specific targets of protein nitration in disease are still missing. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. We previously applied a proteomics approach to determine specific targets of protein oxidation in AD brain, by successfully coupling immunochemical detection of protein carbonyls with two-dimensional polyacrylamide gel electrophoresis and mass spectrometry analysis. In the present study, we extend our investigation of protein oxidative modification in AD brain to targets of protein nitration. The identification of six targets of protein nitration in AD brain provides evidence to the importance of oxidative stress in the progression of this dementing disease and potentially establishes a link between RNS-related protein modification and neurodegeneration. Keywords: Alzheimer's disease, neurodegeneration, 3-nitrotyrosine, proteomics, reactive nitrogen species. 2 leads to formation of peroxynitrate ONOO ) , which, following protonation, generates cytotoxic species that oxidize and nitrate proteins (Beckman 1996). (Formally, the NO 2 added to tyrosine is a nitrite, not nitrate, but the literature has consistently used the latter term, so we shall as well in this paper.)The more common amino acidic targets of oxidation are lysine, histidine, cysteine and methionine (Butterfield and Stadtman 1997), whereas tyrosine is the commonly nitrated amino acid (Souza et al. 2001). In particular, nitration of tyrosine residues is a formal oxidation (Butterfield and Stadtman 1997), a chemical modification that has been used to investigate the mechanism by which tyrosine residues Received November 11, 2002; revised manuscript received February 19, 2003; accepted February 20, 2003. Address correspondence and reprint requests to Professor D. Allan Butterfield, Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506-0055, USA. E-mail: dabcns@uky.eduAbbreviations used: AD, Alzheimer's disease; HCNP, hippocampal cholinergic neurostimulating peptide; IPL, inferior parietal lobule; 3NT, 3-nitrotyrosine; PEBP, phosphatidylethanolamine-binding protein; PBST, phosphate-buffered saline with 0.01% sodium azide and 0.2% Twe...