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Semin Liver Dis 2017; 37(03): 189-197
DOI: 10.1055/s-0037-1604480
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Macrophages in Nonalcoholic Fatty Liver Disease: A Role Model of Pathogenic Immunometabolism

Oliver Krenkel
1   Department of Medicine III, University Hospital Aachen, Aachen, Germany
,
Frank Tacke
1   Department of Medicine III, University Hospital Aachen, Aachen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
28 August 2017 (online)

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Abstract

Nonalcoholic fatty liver disease (NAFLD) and its progressive inflammatory form, nonalcoholic steatohepatitis (NASH), are leading causes of liver cirrhosis and hepatocellular carcinoma. Metabolism and inflammation are intimately interrelated in NAFLD/NASH, as expressed by the term immunometabolism. Hepatic macrophages mediate inflammatory responses during metabolic disorders and can stimulate or dismantle liver fibrosis. Their functional diversity is partly explained by heterogeneous macrophage subsets: tissue-resident Kupffer cells and monocyte-derived macrophages. However, macrophages themselves are altered in their functional polarization by dietary composition and metabolic or inflammatory stimuli in NAFLD. The inflammatory polarization of macrophages correlates with changes in core metabolism pathways like oxidative phosphorylation and glycolysis. The availability of nutrients, such as glucose or fatty acids or oxygen also influences macrophage polarization upon danger signal or cytokine reception. Understanding the interplay of metabolism and macrophage function in NASH may open new approaches to therapeutic targeting of these essential modifiers in metabolic liver diseases.

Keywords

metabolism - immunology - chemokine - steatosis - fibrosis

Key Learning Points

• Immunometabolism comprises the modulation of whole body metabolism by immune cells, as well as the link between inflammatory polarization and cell metabolism.


• Hepatic macrophages mediate the onset as well as the progression of NAFLD from steatosis toward steatohepatitis and fibrosis by releasing inflammatory cytokines, chemokines, and reactive oxygen species.


• Inflammatory polarization of macrophages, following toll-like receptor signaling, is associated with a shift from oxidative phosphorylation and fatty acid oxidation toward glycolysis and the pentose phosphate pathway.


• Liver macrophages are interesting therapeutic targets for treating NASH by either promoting an anti-inflammatory polarization of macrophages or by inhibiting the infiltration of inflammatory monocytes.


 

  • References

  • 1 Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity 2013; 38 (04) 633-643
    CrossrefPubMedGoogle Scholar
  • 2 Heymann F, Tacke F. Immunology in the liver--from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016; 13 (02) 88-110
    CrossrefPubMedGoogle Scholar
  • 3 Ginhoux F, Schultze JL, Murray PJ, Ochando J, Biswas SK. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 2016; 17 (01) 34-40
    CrossrefPubMedGoogle Scholar
  • 4 Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017; 17 (05) 306-321
    CrossrefPubMedGoogle Scholar
  • 5 Heymann F, Peusquens J, Ludwig-Portugall I. , et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 2015; 62 (01) 279-291
    CrossrefPubMedGoogle Scholar
  • 6 Wang Y, van der Tuin S, Tjeerdema N. , et al. Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells. Hepatology 2015; 62 (06) 1710-1722
    CrossrefPubMedGoogle Scholar
  • 7 Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86
    CrossrefPubMedGoogle Scholar
  • 8 Alegre F, Pelegrin P, Feldstein AE. Inflammasomes in liver fibrosis. Semin Liver Dis 2017; 37 (02) 119-127
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012; 143 (05) 1158-1172
    CrossrefPubMedGoogle Scholar
  • 10 Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017; 66 (06) 1300-1312
    CrossrefPubMedGoogle Scholar
  • 11 Zigmond E, Samia-Grinberg S, Pasmanik-Chor M. , et al. Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J Immunol 2014; 193 (01) 344-353
    CrossrefPubMedGoogle Scholar
  • 12 Younossi ZM, Blissett D, Blissett R. , et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016; 64 (05) 1577-1586
    CrossrefPubMedGoogle Scholar
  • 13 Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017; 66 (06) 1138-1153
    CrossrefPubMedGoogle Scholar
  • 14 Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 2016; 13 (04) 196-205
    CrossrefPubMedGoogle Scholar
  • 15 Boutens L, Stienstra R. Adipose tissue macrophages: going off track during obesity. Diabetologia 2016; 59 (05) 879-894
    CrossrefPubMedGoogle Scholar
  • 16 Duarte N, Coelho IC, Patarrão RS, Almeida JI, Penha-Gonçalves C, Macedo MP. How inflammation impinges on NAFLD: a role for Kupffer cells. BioMed Res Int 2015; 2015: 984578
    PubMedGoogle Scholar
  • 17 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489 (7415): 242-249
    CrossrefPubMedGoogle Scholar
  • 18 Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114 (04) 842-845
    CrossrefPubMedGoogle Scholar
  • 19 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (05) 1836-1846
    CrossrefPubMedGoogle Scholar
  • 20 Kazankov K, Barrera F, Møller HJ. , et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int 2016; 36 (10) 1549-1557
    CrossrefPubMedGoogle Scholar
  • 21 Gadd VL, Skoien R, Powell EE. , et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 2014; 59 (04) 1393-1405
    CrossrefPubMedGoogle Scholar
  • 22 Zhang X, Han J, Man K. , et al. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol 2016; 64 (01) 160-170
    CrossrefPubMedGoogle Scholar
  • 23 Tosello-Trampont AC, Krueger P, Narayanan S, Landes SG, Leitinger N, Hahn YS. NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 2016; 63 (03) 799-812
    CrossrefPubMedGoogle Scholar
  • 24 Tomita K, Freeman BL, Bronk SF. , et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep 2016; 6: 28786
    CrossrefPubMedGoogle Scholar
  • 25 Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS One 2016; 11 (07) e0159524
    CrossrefPubMedGoogle Scholar
  • 26 Huang W, Metlakunta A, Dedousis N. , et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010; 59 (02) 347-357
    CrossrefPubMedGoogle Scholar
  • 27 Wehr A, Baeck C, Ulmer F. , et al. Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. PLoS One 2014; 9 (11) e112327
    CrossrefPubMedGoogle Scholar
  • 28 Navarro LA, Wree A, Povero D. , et al. Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J Hepatol 2015; 62 (02) 412-420
    CrossrefPubMedGoogle Scholar
  • 29 Stienstra R, Saudale F, Duval C. , et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 2010; 51 (02) 511-522
    CrossrefPubMedGoogle Scholar
  • 30 Clément S, Juge-Aubry C, Sgroi A. , et al. Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes. Hepatology 2008; 48 (03) 799-807
    CrossrefPubMedGoogle Scholar
  • 31 Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 2016; 13 (03) 316-327
    CrossrefPubMedGoogle Scholar
  • 32 Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 2013; 57 (02) 577-589
    CrossrefPubMedGoogle Scholar
  • 33 Negrin KA, Roth Flach RJ, DiStefano MT. , et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One 2014; 9 (09) e107265
    CrossrefPubMedGoogle Scholar
  • 34 Csak T, Pillai A, Ganz M. , et al. Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis. Liver Int 2014; 34 (09) 1402-1413
    CrossrefPubMedGoogle Scholar
  • 35 Wolf Y, Shemer A, Polonsky M. , et al. Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation. J Exp Med 2017; 214 (04) 905-917
    CrossrefPubMedGoogle Scholar
  • 36 Triantafilou M, Hughes TR, Morgan BP, Triantafilou K. Complementing the inflammasome. Immunology 2016; 147 (02) 152-164
    CrossrefPubMedGoogle Scholar
  • 37 McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity 2014; 41 (01) 36-48
    CrossrefPubMedGoogle Scholar
  • 38 Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (23) 7381-7391
    CrossrefPubMedGoogle Scholar
  • 39 Garcia-Martinez I, Santoro N, Chen Y. , et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 2016; 126 (03) 859-864
    CrossrefPubMedGoogle Scholar
  • 40 Hirsova P, Ibrahim SH, Krishnan A. , et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 2016; 150 (04) 956-967
    CrossrefPubMedGoogle Scholar
  • 41 Sutti S, Jindal A, Locatelli I. , et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 2014; 59 (03) 886-897
    CrossrefPubMedGoogle Scholar
  • 42 Weiskirchen R, Tacke F. Liver fibrosis: from pathogenesis to novel therapies. Dig Dis 2016; 34 (04) 410-422
    CrossrefPubMedGoogle Scholar
  • 43 Baeck C, Wei X, Bartneck M. , et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 2014; 59 (03) 1060-1072
    CrossrefPubMedGoogle Scholar
  • 44 Baeck C, Wehr A, Karlmark KR. , et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 2012; 61 (03) 416-426
    CrossrefPubMedGoogle Scholar
  • 45 Mulder P, van den Hoek AM, Kleemann R. The CCR2 inhibitor propagermanium attenuates diet-induced insulin resistance, adipose tissue inflammation and non-alcoholic steatohepatitis. PLoS One 2017; 12 (01) e0169740
    CrossrefPubMedGoogle Scholar
  • 46 Ramachandran P, Pellicoro A, Vernon MA. , et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (46) E3186-E3195
    CrossrefPubMedGoogle Scholar
  • 47 Eom DS, Parichy DM. A macrophage relay for long-distance signaling during postembryonic tissue remodeling. Science 2017; 355 (6331): 1317-1320
    CrossrefPubMedGoogle Scholar
  • 48 Geeraerts X, Bolli E, Fendt SM, Van Ginderachter JA. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol 2017; 8: 289
    PubMedGoogle Scholar
  • 49 Bieghs V, Rensen PC, Hofker MH, Shiri-Sverdlov R. NASH and atherosclerosis are two aspects of a shared disease: central role for macrophages. Atherosclerosis 2012; 220 (02) 287-293
    CrossrefPubMedGoogle Scholar
  • 50 Ratziu V, Harrison SA, Francque S. , et al; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150 (05) 1147-1159.e5
    CrossrefPubMedGoogle Scholar
  • 51 Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A. , et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 2008; 7 (06) 496-507
    CrossrefPubMedGoogle Scholar
  • 52 Staels B, Rubenstrunk A, Noel B. , et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58 (06) 1941-1952
    CrossrefPubMedGoogle Scholar
  • 53 Banini BA, Sanyal AJ. Current and future pharmacologic treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol 2017; 33 (03) 134-141
    CrossrefPubMedGoogle Scholar
  • 54 Iacobini C, Menini S, Ricci C. , et al. Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. J Hepatol 2011; 54 (05) 975-983
    CrossrefPubMedGoogle Scholar
  • 55 Li P, Liu S, Lu M. , et al. Hematopoietic-derived galectin-3 causes cellular and systemic insulin resistance. Cell 2016; 167 (04) 973-984.e12
    CrossrefPubMedGoogle Scholar
  • 56 Harrison SA, Marri SR, Chalasani N. , et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther 2016; 44 (11-12): 1183-1198
    CrossrefPubMedGoogle Scholar
  • 57 Loomba R, Lawitz E, Mantry PS. , et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. Hepatology 2016; 64: 1119A-1120A
    PubMedGoogle Scholar
  • 58 Sanyal AJ, Ratziu V, Harrison S. , et al. Cenicriviroc placebo for the treatment of non-alcoholic steatohepatitis with liver fibrosis: results from the year 1 primary analysis of the Phase 2b CENTAUR study. Hepatology 2016; 64: 1118A-1119A
    CrossrefPubMedGoogle Scholar
  • 59 Bäckhed F, Ding H, Wang T. , et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101 (44) 15718-15723
    CrossrefPubMedGoogle Scholar
  • 60 McPhee JB, Schertzer JD. Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation. Clin Sci (Lond) 2015; 129 (12) 1083-1096
    CrossrefPubMedGoogle Scholar
  • 61 Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol 2012; 18 (21) 2609-2618
    CrossrefPubMedGoogle Scholar
  • 62 Schneider KM, Bieghs V, Heymann F. , et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 2015; 62 (05) 1405-1416
    PubMedGoogle Scholar
  • 63 Imajo K, Fujita K, Yoneda M. , et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab 2012; 16 (01) 44-54
    CrossrefPubMedGoogle Scholar
  • 64 Csak T, Velayudham A, Hritz I. , et al. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 2011; 300 (03) G433-G441
    CrossrefPubMedGoogle Scholar
  • 65 Miura K, Kodama Y, Inokuchi S. , et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 2010; 139 (01) 323-34.e7
    CrossrefPubMedGoogle Scholar
  • 66 Wiest R, Albillos A, Trauner M, Bajaj J, Jalan R. ‘Targeting the gut-liver axis in liver disease’. J Hepatol 2017; S0168-8278(17)32016-0 [E-Pub ahead of print]. Doi: 10.1016/j.jhep.2017.05.007
    PubMedGoogle Scholar
  • 67 O'Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med 2016; 213 (01) 15-23
    CrossrefPubMedGoogle Scholar
  • 68 Rodríguez-Prados JC, Través PG, Cuenca J. , et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 2010; 185 (01) 605-614
    CrossrefPubMedGoogle Scholar
  • 69 O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 2013; 493 (7432): 346-355
    CrossrefPubMedGoogle Scholar
  • 70 Haschemi A, Kosma P, Gille L. , et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 2012; 15 (06) 813-826
    CrossrefPubMedGoogle Scholar
  • 71 Imtiyaz HZ, Williams EP, Hickey MM. , et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 2010; 120 (08) 2699-2714
    CrossrefPubMedGoogle Scholar
  • 72 Locasale JW, Cantley LC. Metabolic flux and the regulation of mammalian cell growth. Cell Metab 2011; 14 (04) 443-451
    CrossrefPubMedGoogle Scholar
  • 73 Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci 2004; 75 (06) 639-653
    CrossrefPubMedGoogle Scholar
  • 74 West AP, Brodsky IE, Rahner C. , et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472 (7344): 476-480
    CrossrefPubMedGoogle Scholar
  • 75 Jha AK, Huang SC, Sergushichev A. , et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 2015; 42 (03) 419-430
    CrossrefPubMedGoogle Scholar
  • 76 Huang SC, Everts B, Ivanova Y. , et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 2014; 15 (09) 846-855
    CrossrefPubMedGoogle Scholar
  • 77 Nomura M, Liu J, Rovira II. , et al. Fatty acid oxidation in macrophage polarization. Nat Immunol 2016; 17 (03) 216-217
    CrossrefPubMedGoogle Scholar
  • 78 Leroux A, Ferrere G, Godie V. , et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol 2012; 57 (01) 141-149
    CrossrefPubMedGoogle Scholar
  • 79 Xue J, Schmidt SV, Sander J. , et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014; 40 (02) 274-288
    CrossrefPubMedGoogle Scholar
  • 80 Hodson L, Skeaff CM, Fielding BA. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res 2008; 47 (05) 348-380
    CrossrefPubMedGoogle Scholar
  • 81 Im SS, Yousef L, Blaschitz C. , et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 2011; 13 (05) 540-549
    CrossrefPubMedGoogle Scholar
  • 82 Martínez-Micaelo N, González-Abuín N, Pinent M, Ardévol A, Blay M. Dietary fatty acid composition is sensed by the NLRP3 inflammasome: omega-3 fatty acid (DHA) prevents NLRP3 activation in human macrophages. Food Funct 2016; 7 (08) 3480-3487
    CrossrefPubMedGoogle Scholar
  • 83 Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells. J Nutr Biochem 2016; 34: 1-7
    CrossrefPubMedGoogle Scholar
  • 84 Bieghs V, Hendrikx T, van Gorp PJ. , et al. The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 2013; 144 (01) 167-178.e1
    CrossrefPubMedGoogle Scholar
  • 85 Johnson AR, Qin Y, Cozzo AJ. , et al. Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 2016; 5 (07) 506-526
    CrossrefPubMedGoogle Scholar
  • 86 Souza CO, Teixeira AA, Biondo LA, Silveira LS, Calder PC, Rosa Neto JC. Palmitoleic acid reduces the inflammation in LPS-stimulated macrophages by inhibition of NFκB, independently of PPARs. Clin Exp Pharmacol Physiol 2017; 44 (05) 566-575
    CrossrefPubMedGoogle Scholar
  • 87 Weavers H, Evans IR, Martin P, Wood W. Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 2016; 165 (07) 1658-1671
    CrossrefPubMedGoogle Scholar
  • 88 Bowdish DM, Loffredo MS, Mukhopadhyay S, Mantovani A, Gordon S. Macrophage receptors implicated in the “adaptive” form of innate immunity. Microbes Infect 2007; 9 (14-15): 1680-1687
    CrossrefPubMedGoogle Scholar
  • 89 A-Gonzalez N, Quintana JA, García-Silva S. , et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med 2017; 214 (05) 1281-1296
    CrossrefPubMedGoogle Scholar
  • 90 Huang SC, Smith AM, Everts B. , et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 2016; 45 (04) 817-830
    CrossrefPubMedGoogle Scholar
  • 91 Albert V, Svensson K, Shimobayashi M. , et al. mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue. EMBO Mol Med 2016; 8 (03) 232-246
    CrossrefPubMedGoogle Scholar
  • 92 Covarrubias AJ, Aksoylar HI, Yu J. , et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife 2016; 5: e11612
    CrossrefPubMedGoogle Scholar