Y, activated macrophages is usually divided in two subgroups in vitro: these with proinflammatory activity (M1) involved in first line of defense against bacterial infection, and those with anti-inflammatory activity (M2) that regulate tissue repair and wound healing (116), even though that is an oversimplification with the functional diversity occurring in vivo. Metabolic reprogramming of immune cells is essential for both pro- and anti-inflammatory responses as well as a vast spectrum of metabolic statuses accompanies the complexity of phenotypes [reviewed in (117, 118)]. Generally, an increase in glycolysis and in glucose uptake is generally associated to an M1 phenotype (119), even though M2 macrophages depend on intact TCA cycle and OXPHOS as significant supply of ATP by means of electron transport chain and ATP synthase (120, 121). On the other hand, in addition to an augmented mitochondrial metabolism, alternatively activated macrophages can also use glycolysis when OXPHOS is disrupted (122). One more essential pathway may be the pentose phosphate pathway (PPP), which generates pentoses, 5-ribose phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is crucial in activated M1 macrophages because it fuels ROS production by NADPH oxidase (123), even ifFrontiers in Immunology | www.frontiersin.orgJuly 2019 | Volume ten | ArticleAudrito et al.NAD-Dependent Enzymes in Immune Regulationother groups demonstrated that NADPH and NADPH oxidase play a role even in M2 differentiation (124). Concerning lipid metabolism, fatty acid synthesis is coupled to pro-inflammatory activity of macrophages, although beta-oxidation is common of antiinflammatory macrophages (117). The enhance of glycolysis associated with M1 activation of macrophages is orchestrated by the transcription PC Biotin-PEG3-NHS ester MedChemExpress element HIF-1. When cells encounter low oxygen levels HIF-1 is stabilized and, upon binding on the HIF-1 subunit, initiates the transcription of genes like glucose transporter and glycolytic enzymes (125, 126). NF-kB is needed for transcriptional activation of HIF-1 (127); whereas, in M2 macrophages, genes involved in metabolic reprogramming are largely controlled by STAT6 and peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1) (128). Each iNAMPT and eNAMPT influence basic monocytemacrophages processes for instance differentiation, polarization and migration, even if the exact role of iNAMPTeNAMPT in the procedure of Oxyfluorfen Description myelopoiesis is incompletely elucidated so far (12931) as summarized in Figure three. One example is, NAMPT includes a function in the induction of an immunosuppressive and tumor-promoting microenvironment in chronic lymphocytic leukemia, exactly where eNAMPT is important for the differentiation of monocytes toward tumor-supporting immunosuppresive M2 macrophage, promoting their differentiation, and polarization in tumor-supportive cells including TAMs (130). Recently, it was demonstrated that iNAMPT acts also on MDSCs, exactly where NAMPT inhibits CXCR4 transcription, via NADSIRT1HIF-1 axis, and this, in turn, results in a mobilization of MDSCs and enhances their production of suppressive nitric oxide (132). Modifications in NAD levels characterize various stage of macrophage polarization: in general, greater levels of NAD are typical of classically activated pro-inflammatory macrophages (M1), while NAD levels are reduce in alternatively activated antiinflammatory macrophages (M2). The NAMPTNADSIRT1 axis appears to play a relevant role in myeloid cell functions as shown by the fact that efficient activation.
