Immunobiology 224 (2019) 242–253 Contents lists available at ScienceDirect Immunobiology journal homepage: www.elsevier.com/locate/imbio Review Reactive oxygen species (ROS) in macrophage activation and function in diabetes T Erika Rendraa,b, Vladimir Riabovb,c, Dieuwertje M. Mosselb, Tatyana Sevastyanovab,c, ⁎ Martin C. Harmsena, Julia Kzhyshkowskab,c,d, a Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, the Netherlands b The Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Germany c Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia d Red Cross Blood Service Baden-Württemberg–Hessen, Germany ARTICLE INFO ABSTRACT Keywords: In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular Reactive oxygen species complications of diabetes. Recent studies have shown that ROS formation is exacerbated in diabetic monocytes Macrophage and macrophages due to a glycolytic metabolic shift. Macrophages are important players in the progression of Diabetes diabetes and promote inflammation through the release of pro-inflammatory cytokines and proteases. Because Obesity ROS is an important mediator for the activation of pro-inflammatory signaling pathways, obesity and hy- Hyperglycemia perglycemia-induced ROS production may favor induction of M1-like pro-inflammatory macrophages during Inflammation κ Metabolism diabetes onset and progression. ROS induces MAPK, STAT1, STAT6 and NF B signaling, and interferes with macrophage differentiation via epigenetic (re)programming. Therefore, a comprehensive understanding of the impact of ROS on macrophage phenotype and function is needed in order to improve treatment of diabetes and its vascular complications. In the current comprehensive review, we dissect the role of ROS in macrophage polarization, and analyze how ROS production links metabolism and inflammation in diabetes and its compli- cations. Finally, we discuss the contribution of ROS to the crosstalk between macrophages and endothelial cells in diabetic complications. 1. Introduction patients and their families both morally and economically, and weighs down the national economics (Anon, 2018). Therefore, effective med- Diabetes mellitus is a major public health problem worldwide which ical intervention to treat this disease is of critical importance. seriously impairs the quality of life of the patients. The Global Diabetes Recent studies show that oxidative stress is a major mediator that Report released by World Health Organization states that the number of underlies diabetic complications (Pitocco et al., 2013; Giacco, 2011). In diabetics has increased from 108 million in 1980 to 422 million in hyperglycemia-sensitive cells, such as endothelial cells, the excessive 2014. The global disease prevalence has grown from 4.7% to 8.5% in load of glucose triggers the formation of ROS in mitochondria which in adult population, with higher prevalence in low to middle-income turn impairs mitochondrial function (Brownlee, 2001; Pitocco et al., countries (Anon, 2018). Chronic untreated diabetes causes various 2013; Giacco, 2011). Due to its high reactivity, the ROS reacts with macro- and micro-vascular complications, such as atherosclerosis, dia- various cellular constituents, including DNA, lipids and proteins betic nephropathy, diabetic retinopathy, neural damage while poor causing cellular damage. Furthermore, excessive ROS activates pro-in- perfusion of extremities often requires their amputation (Brownlee, flammatory transcription factors such as NFκB and AP-1 that upregulate 2001). Diabetic retinopathy is an important cause of blindness expression of pro-inflammatory chemokines/cytokines and adhesion (Kowluru and Chan, 2007), while diabetic nephropathy is one of the molecules. Activated endothelial cells attract monocytes that further most serious complications of diabetes as well as leading causes of end- augment inflammation which promotes macrovascular and micro- stage renal disease (Kowluru and Chan, 2007; Saran et al., 2015). vascular injury (Pitocco et al., 2013). ROS has also been implicated in Diabetes and its associated complications are a serious burden for the epigenetic modifications involved in the maintenance of pro- ⁎ Corresponding author at: Dept. of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer Ufer 1-3, D-68167, Mannheim, Germany. E-mail address: [email protected] (J. Kzhyshkowska). https://doi.org/10.1016/j.imbio.2018.11.010 Received 13 September 2018; Received in revised form 27 November 2018; Accepted 27 November 2018 Available online 01 December 2018 0171-2985/ © 2018 Published by Elsevier GmbH. E. Rendra et al. Immunobiology 224 (2019) 242–253 inflammatory response (El-Osta, 2012a). stimulation, such as viral and bacterial infection, both cytosolic and In addition to endothelial cells, diabetic conditions also trigger ROS membrane subunits cooperate to produce ROS. In phagocytes such as formation in macrophages (Tesch, 2007). The diabetes-induced secre- macrophages and neutrophils, NOX is important for oxidative burst tion of monocyte chemotactic protein CCL2 (MCP1) by endothelium which allows phagocytes to generate high levels of ROS to kill micro- attracts monocytes whereas upregulated endothelial surface expression organisms (Panday et al., 2015; Lambeth, 2004). Similar to mitochon- of adhesion molecule VCAM promotes their adhesion and diapedesis dria, NOX also produces ROS in the form of superoxide which is further (Tesch, 2007). Transmigrated monocytes differentiate into macro- converted by SOD1 into H2O2 (Reczek and Chandel, 2015). In addition phages and further exacerbate inflammation by mediating tissue injury to NOX, during respiratory burst in phagocytes, ROS is also produced and secreting pro-inflammatory cytokines and proteases as well as through inducible nitric oxide synthase (iNOS) by catalyzing the for- producing increased ROS levels in the tissues (Tesch, 2007). Hy- mation of robust nitric oxide which reacts with superoxide anion re- perglycemia causes mitochondrial dysfunction in endothelial cells and sulting in a very reactive oxidant peroxynitrite (Lo Faro et al., 2014; macrophages and aberrant activation of cytoplasmic NADPH oxidases Fang, 2004). In contrast, in vascular endothelial cells, endothelial nitric (NOX) that together exacerbate ROS production (Widlansky et al., oxide synthase (eNOS) is a major source of nitric oxide (Fish and 2011; Huang et al., 2011). In contrast to well-regulated ROS production Marsden, 2006). In the absence of its cofactor tetrahydrobiopterin in anti-microbial response, metabolically-generated ROS in diabetic (BH4), uncoupled eNOS switches to NADPH-dependent superoxide macrophages is more erratic and dysregulated. Its production is asso- anion production, which contributes to endothelial dysfunction in ciated with promotion of M1-like macrophage phenotype that favors diabetes and cardiovascular diseases (Karbach et al., 2014; Luo et al., the progression of diabetic complications (Kumar et al., 2016). Here, we 2014). review ROS biology in diabetes and the influence of ROS on macro- Peroxisomes generate ROS in the form of H2O2 as a by-product of phage polarization. The second part discusses the function of macro- long chain fatty acid oxidation while the endoplasmic reticulum gen- phages in diabetic disease progression and the role of macrophage- erates ROS as by-product of protein oxidation. Besides these four me- produced ROS as a detrimental factor in diabetic complications. chanisms, a broad range of enzymes is also able to generate ROS such as cytochrome P450 in mitochondria and ER, and lipoxygenases in cell 2. Biology of ROS membrane and cytosol (Holmström and Finkel, 2014). The contribution of these sources to oxidative stress varies depending on the stimuli by Oxidative stress is implicated in the pathogenesis of severe diseases which ROS production is triggered, such as hyperglycemia, free fatty such as cancer, diabetes, auto-immune and neuro-degenerative dis- acids, LPS induction as well as a broad range of cytokines (Reczek and eases. Oxidative stress is caused by intracellular presence of reactive Chandel, 2015). A common denominator of these additional ROS gen- oxygen species (ROS) which overcomes the natural anti-oxidant defense erating mechanisms is that all of them are associated with metabolic of the cell (Schieber and Chandel, 2014). The strong oxidative prop- pathways. erties of ROS result in damage of intracellular constituents such as proteins, lipids and nucleic acids. The resulting modifications alter the 2.2. ROS in cell signaling structure and therefore the function of these molecules. ROS is mostly produced as a by-product of various cellular processes in multiple forms Although high levels of ROS are deleterious, intermediate levels of •− including superoxide (O2 ), hydrogen peroxide (H2O2), and hydroxyl ROS serve as an important short-lived second messenger in cell sig- •− radical (OH ). In general the balance between ROS formation and its naling by oxidizing the thiol group in cysteine residues of a protein. In elimination is tilted under stressed conditions such as diabetes which general, oxidized cysteine residues alter the structure and consequently cause upregulated ROS formation (Schieber and Chandel, 2014; the function