Clinical Science (2017) 131 1329–1342 DOI: 10.1042/CS20170220 * These authors contributed equally to this work. This review is dedicated to the late Prof. Eric A. Newsholme and his pioneering original immunometabolism studies. Received: 16 March 2017 Revised: 16 March 2017 Accepted: 22 March 2017 Version of Record published: 7 May 2017 Review Article A past and present overview of macrophage metabolism and functional outcomes Rui Curi 1 * , Renata de Siqueira Mendes 1 * , Luiz Aur ´ elio de Campos Crispin 2 , Giuseppe Danilo Norata 3,4 , Sandra Coccuzzo Sampaio 2,5 and Philip Newsholme 3 1 Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S ˜ ao Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-900, Brazil; 2 Laboratory of Pathophysiology, Butantan Institute, Av. Vital Brazil, 1500, SP 05503-900, S˜ ao Paulo, Brazil; 3 School of Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, Australia; 4 Department of Pharmacological and Biomolecular Sciences, Universit ` a degli Studi di Milano, Milan, Italy; 5 Department of Pharmacology, Institute of Biomedical Sciences, University of S ˜ ao Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-900, Brazil Correspondence: Philip Newsholme (Philip.Newsholme@curtin.edu.au) In 1986 and 1987, Philip Newsholme et al. reported macrophages utilize glutamine, as well as glucose, at high rates. These authors measured key enzyme activities and consumption and production levels of metabolites in incubated or cultured macrophages isolated from the mouse or rat intraperitoneal cavity. Metabolic pathways essential for macrophage func- tion were then determined. Macrophages utilize glucose to generate (i) ATP in the pathways of glycolysis and mitochondrial oxidative phosphorylation, (ii) glycerol 3-phosphate for the synthesis of phospholipids and triacylglycerols, (iii) NADPH for the production of reactive oxygen species (ROS) and (iv) ribose for the synthesis of RNA and subsequently production and secretion of protein mediators (e.g. cytokines). Glutamine plays an essential role in mac- rophage metabolism and function, as it is required for energy production but also provides nitrogen for synthesis of purines, pyrimidines and thus RNA. Macrophages also utilize fatty acids for both energy production in the mitochondria and lipid synthesis essential to plasma membrane turnover and lipid meditator production. Recent studies utilizing metabolomic approaches, transcriptional and metabolite tracking technologies have detailed mitochon- drial release of tricarboxylic acid (TCA) intermediates (e.g. citrate and succinate) to the cytosol, which then regulate pro-infammatory responses. Macrophages can reprogramme their metabolism and function according to environmental conditions and stimuli in order to polarize phenotype so generating pro- or anti-infammatory cells. Changes in macrophage metabolism result in modifed function/phenotype and vice versa. The plasticity of macro- phage metabolism allows the cell to quickly respond to changes in environmental conditions such as those induced by hormones and/or infammation. A past and present overview of macrophage metabolism and impact of endocrine regulation and the relevance to human disease are described in this review. Macrophage function and activation Macrophages are uniquely equipped to detect and respond to tissue invasion by infectious organisms and to tissue injury through various scavenger, pattern recognition and phagocytic receptors [1,2]. Mac- rophages rapidly and efficiently remove cellular debris, generated during wound repair, tissue remodel- ling and from apoptosis [3]. Trauma or stress-induced necrosis also produces cellular debris that must be cleared by macrophages. The process of waste removal requires marked alterations in phagocyte physiology including changed surface protein expression, production of cytokines and pro-inflammatory mediators, and cell metabolism [3]. These changes occur due to the fact that, in many cases, the debris from cell necrosis is loaded with endogenous danger signals such as heat shock proteins, nuclear proteins, histones, DNA and other nucleotides [4], which are recognized by macrophages. Macrophages can also c  2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society. 1329 Downloaded from https://portlandpress.com/clinsci/article-pdf/131/12/1329/448950/cs1311329.pdf by guest on 08 June 2020