Febs Letters

doi: 10.1002/1873-3468.12870pmid: N/A

doi: 10.1002/1873-3468.12409pmid: N/A

Nagy, Laszlo; Ellmeier, Wilfried

doi: 10.1002/1873-3468.12857pmid: 29023724

Treuter, Eckardt; Fan, Rongrong; Huang, Zhiqiang; Jakobsson, Tomas; Venteclef, Nicolas

doi: 10.1002/1873-3468.12850pmid: 28902388

Macrophage differentiation and signal responses are coordinated by closely linked transcriptional and epigenomic mechanisms that trigger gene expression. In contrast to well‐characterized transcriptional activation pathways in response to diverse metabolic and inflammatory signals, we just begin appreciating that transcriptional repression is equally important. Here, we will highlight macrophage pathways that are controlled by multifaceted repression events, along with a discussion of underlying regulatory mechanisms and components. We will particularly discuss pro‐ versus anti‐inflammatory action of a fundamental corepressor complex, transcription factor cross‐talk, repression at enhancers and during elongation, and diverse corepressor knockout mouse models. We will finally emphasize how alterations of macrophage repression pathways in humans contribute to, or even cause, metabolic inflammatory diseases such as obesity and type 2 diabetes.

Schulman, Ira G.

doi: 10.1002/1873-3468.12702pmid: 28555747

The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit proinflammatory gene expression. This Review will highlight recent studies that connect LXR‐dependent control of lipid metabolism to regulation of the immune response.

Ryan, Dylan Gerard; O'Neill, Luke A. J.

doi: 10.1002/1873-3468.12744pmid: 28685841

The Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.

Juban, Gaëtan; Chazaud, Bénédicte

doi: 10.1002/1873-3468.12703pmid: 28555751

Macrophages are highly versatile cells that are involved both in the mounting and the resolution of inflammatory responses. Besides their properties in innate immunity to fight against pathogens, macrophages are essential for tissue repair, during which they adopt sequential inflammatory status. While the acquisition of some canonical polarized inflammatory statuses in vitro (M1/M2) is beginning to be understood at the molecular level, the regulation of macrophage skewing in vivo has been less investigated. Immunometabolism, in particular, is an emerging field, and most of the studies so far have investigated the control of macrophage polarization using in vitro set‐ups. In this context, skeletal muscle regeneration is an excellent paradigm to study tissue repair, since the sequential steps of inflammatory response and tissue repair are well characterized. In this Review, after introducing macrophage populations and functions during skeletal muscle regeneration, we present the current knowledge on the metabolic regulation of macrophage inflammatory status, with particular emphasis on the comparison between in vitro and in vivo models of macrophage activation. We also discuss the metabolic regulation of macrophages in vivo during skeletal muscle regeneration.

Rabold, Katrin; Netea, Mihai G.; Adema, Gosse J.; Netea‐Maier, Romana T.

doi: 10.1002/1873-3468.12771pmid: 28771701

Macrophages are innate immune cells that play a role not only in host defense against infections, but also in the pathophysiology of autoimmune and autoinflammatory disorders, as well as cancer. An important feature of macrophages is their high plasticity, with high ability to adapt to environmental changes by adjusting their cellular metabolism and immunological phenotype. Macrophages are one of the most abundant innate immune cells within the tumor microenvironment that have been associated with tumor growth, metastasis, angiogenesis and poor prognosis. In the context of cancer, however, so far little is known about metabolic changes in macrophages, which have been shown to determine functional fate of the cells in other diseases. Here, we review the current knowledge regarding the cellular metabolism of tumor‐associated macrophages (TAMs) and discuss its implications for cell function. Understanding the regulation of the cellular metabolism of TAMs may reveal novel therapeutic targets for treatment of malignancies.

Bories, Gael F. P.; Leitinger, Norbert

doi: 10.1002/1873-3468.12786pmid: 28796886

A key aspect of atherosclerosis is the maladaptive inflammatory response to lipoprotein accumulation in the artery. The failure to decrease lipid accumulation, to clear apoptotic cells, and to resolve inflammation ultimately leads to macrophage accumulation within the vascular wall [Thorp EB (2010) Apoptosis 15, 1124–1136; Moore K et al. (2013) Nat Rev Immunol 13, 709–721; Moore KJ and Tabas I (2011) Cell 145, 341–355; Ley K et al. (2011) Arterioscler Thromb Vasc Biol 31, 1506–1516]. Several subsets of macrophages are found inside atherosclerotic plaques [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17; Leitinger N and Schulman IG (2013) Arterioscler Thromb Vasc Biol 33, 1120–1126; Mantovani A et al. (2009) Arterioscler Thromb Vasc Biol 29, 1419–1423]: Proinflammatory M1‐like macrophages potentially participate in atherosclerosis initiation and progression; M2‐like macrophages are thought to be protective due to their anti‐inflammatory and profibrotic properties, presumably stabilizing the plaque [Chistiakov DA et al. (2015) Int J Cardiol 184, 436–445; Gordon S (2003) Nat Rev Immunol 3, 23–35]; Mox macrophages develop in response to oxidized phospholipids and present a glutathione‐ and potentially redox‐regulating phenotype [Kadl A et al. (2010) Circ Res 107, 737–746]; Mhem macrophages are found in areas of plaque hemorrhage [Boyle JJ et al. (2009) Am J Pathol 174, 1097–1108; Boyle JJ et al. (2012) Circ Res 110, 20–33] where they are involved in heme clearance. Recent evidence suggests that the relative abundance of these macrophage subsets is a better indicator of plaque progression and stability than the total number of lesion macrophages [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17]. Over the last few years, findings in the area of immunometabolism established a link between the metabolic state of the different macrophage phenotypes and their functions [O'Neill LAJ and Pearce EJ (2016) J Exp Med 213, 15–23]. However, the effect of metabolic changes in macrophages on atherosclerotic plaque progression and stability is not well understood and an area of intensive study. In this review, we will summarize and critically discuss recent developments in the field of macrophage metabolism in the context of atherosclerosis to guide future investigation in this area.

Caputo, Tiziana; Gilardi, Federica; Desvergne, Béatrice

doi: 10.1002/1873-3468.12742pmid: 28677122

The close association of obesity with an increased risk of metabolic diseases, such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease, is now well established. In this review, we aim first to describe the inflammatory process activated in response to overnutrition, especially in the liver and the adipose tissue. We then discuss the systemic effects of low‐grade inflammation on the onset of insulin resistance. Particular attention is given to a series of very recent reports that identify not only processes but also molecules (lipids and metabolites) that interfere with the normal insulin signaling. Finally, special notes concerning the roles of peroxisome proliferator‐activated receptors in the various processes will be made.