Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2021; 121(11): 1464-1475
DOI: 10.1055/s-0041-1726346

Blood Cells, Inflammation and Infection

Methylglyoxal Drives a Distinct, Nonclassical Macrophage Activation Status

Foivos-Filippos Tsokanos^*

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

,

Carolin Muley^*

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

⁴Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

,

Sajjad Khani^**

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

⁴Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

,

Daniela Hass^**

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

,

Thomas Fleming

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

,

Gretchen Wolff

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

,

Alexander Bartelt

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

⁴Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany

⁵German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Technische Universität München, Munich, Germany

,

Peter Nawroth

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

,

Stephan Herzig

¹Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

³German Center for Diabetes Research, Neuherberg, Germany

⁶Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany

› Author Affiliations

Abstract

Metabolic complications in diabetic patients are driven by a combination of increased levels of nutrients and the presence of a proinflammatory environment. Methylglyoxal (MG) is a toxic byproduct of catabolism and has been strongly associated with the development of such complications. Macrophages are key mediators of inflammatory processes and their contribution to the development of metabolic complications has been demonstrated. However, a direct link between reactive metabolites and macrophage activation has not been demonstrated yet. Here, we show that acute MG treatment activated components of the p38 MAPK pathway and enhanced glycolysis in primary murine macrophages. MG induced a distinct gene expression profile sharing similarities with classically activated proinflammatory macrophages as well as metabolically activated macrophages usually found in obese patients. Transcriptomic analysis revealed a set of 15 surface markers specifically upregulated in MG-treated macrophages, thereby establishing a new set of targets for diagnostic or therapeutic purposes under high MG conditions, including diabetes. Overall, our study defines a new polarization state of macrophages that may specifically link aberrant macrophage activation to reactive metabolites in diabetes.

Keywords

Keywords

methylglyoxal - macrophage polarization - diabetes - metabolic activation

References
1 Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell 2018; 172 (1–2): 22-40
2 International Diabetes Federation, IDF Diabetes Atlas, 8th Edn.. International Diabetes Federation. 2017 . Accessed October 1, 2019 at: http://www.diabetesatlas.org
3 American Diabetes Association. Diagnosis and classification of diabetes mellitus. 2009; 32 (Suppl. 01) S62-S67
4 Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017; 542 (7640): 177-185
5 Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol 2018; 9 (01) 1-58
6 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116 (11) 3015-3025
7 Lee JY, Ye J, Gao Z. et al. Reciprocal modulation of toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 2003; 278 (39) 37041-37051
8 Kratz M, Coats BR, Hisert KB. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20 (04) 614-625
9 Thornalley PJ. Dicarbonyl intermediates in the maillard reaction. Ann N Y Acad Sci 2005; 1043: 111-117
10 Matafome P, Rodrigues T, Sena C, Seiça R. Methylglyoxal in metabolic disorders: facts, myths, and promises. Med Res Rev 2017; 37 (02) 368-403
11 Skapare E, Konrade I, Liepinsh E. et al. Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients. J Diabetes Complications 2013; 27 (03) 262-267
12 Maessen DEM, Stehouwer CDA, Schalkwijk CG. The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases. Clin Sci (Lond) 2015; 128 (12) 839-861
13 Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet 2017; 389 (10085): 2239-2251
14 Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 1999; 48 (01) 198-202
15 Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH. Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem 2011; 44 (04) 307-311
16 Nemet I, Turk Z, Duvnjak L, Car N, Varga-Defterdarović L. Humoral methylglyoxal level reflects glycemic fluctuation. Clin Biochem 2005; 38 (04) 379-383
17 Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008; 8 (12) 923-934
18 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: 1-19
19 Byles V, Covarrubias AJ, Ben-Sahra I. et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 2013; 4: 2834
20 McGuire VA, Gray A, Monk CE. et al. Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling. Mol Cell Biol 2013; 33 (21) 4152-4165
21 Katholnig K, Kaltenecker CC, Hayakawa H. et al. p38α senses environmental stress to control innate immune responses via mechanistic target of rapamycin. J Immunol 2013; 190 (04) 1519-1527
22 Rabbani N, Thornalley PJ. Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nat Protoc 2014; 9 (08) 1969-1979
23 Han Y, Randell E, Vasdev S. et al. Plasma advanced glycation endproduct, methylglyoxal-derived hydroimidazolone is elevated in young, complication-free patients with Type 1 diabetes. Clin Biochem 2009; 42 (7–8): 562-569
24 Ogawa S, Nakayama K, Nakayama M. et al. Methylglyoxal is a predictor in type 2 diabetic patients of intima-media thickening and elevation of blood pressure. Hypertension 2010; 56 (03) 471-476
25 Bierhaus A, Fleming T, Stoyanov S. et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012; 18 (06) 926-933
26 Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact 2008; 171 (03) 251-271
27 Li H, O'Meara M, Zhang X. et al. Ameliorating methylglyoxal-induced progenitor cell dysfunction for tissue repair in diabetes. Diabetes 2019; 68 (06) 1287-1302
28 Zheng Q, Omans ND, Leicher R. et al. Reversible histone glycation is associated with disease-related changes in chromatin architecture. Nat Commun 2019; 10 (01) 1289
29 Luengo A, Abbott KL, Davidson SM. et al. Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer. Nat Commun 2019; 10 (01) 5604
30 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
31 Van den Bossche J, Baardman J, de Winther MPJ. Metabolic characterization of polarized M1 and M2 bone marrow-derived macrophages using real-time extracellular flux analysis. J Vis Exp 2015; 2015 (105) 1-7
32 Van den Bossche J, Baardman J, Otto NA. et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Reports 2016; 17 (03) 684-696
33 Allaman I, Bélanger M, Magistretti PJ. Methylglyoxal, the dark side of glycolysis. Front Neurosci 2015; 9 (FEB): 23
34 Corrêa-da-Silva F, Pereira JAS, de Aguiar CF, de Moraes-Vieira PMM. Mitoimmunity-when mitochondria dictates macrophage function. Cell Biol Int 2018; 42 (06) 651-655
35 Molocea C-EE, Tsokanos F-FF, Herzig S. Exploiting common aspects of obesity and cancer cachexia for future therapeutic strategies. Curr Opin Pharmacol 2020; 53: 101-116
36 Yoon BR, Oh YJ, Kang SW, Lee EB, Lee WW. Role of SLC7A5 in metabolic reprogramming of human monocyte/macrophage immune responses. Front Immunol 2018; 9 (JAN): 53
37 Kold-Christensen R, Johannsen M. Methylglyoxal metabolism and aging-related disease: moving from correlation toward causation. Trends Endocrinol Metab 2020; 31 (02) 81-92
38 Beisswenger PJ. Methylglyoxal in diabetes: link to treatment, glycaemic control and biomarkers of complications. Biochem Soc Trans 2014; 42 (02) 450-456
39 Groener JB, Oikonomou D, Cheko R. et al. Methylglyoxal and advanced glycation end products in patients with diabetes - what we know so far and the missing links. Exp Clin Endocrinol Diabetes 2019; 127 (08) 497-504
40 Hanssen NMJ, Scheijen JLJM, Jorsal A. et al. Higher plasma methylglyoxal levels are associated with incident cardiovascular disease in individuals with type 1 diabetes: a 12-year follow-up study. Diabetes 2017; 66 (08) 2278-2283
41 Andersen ST, Witte DR, Dalsgaard EM. et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: Addition-Denmark. Diabetes Care 2018; 41 (05) 1068-1075
42 Brings S, Fleming T, De Buhr S. et al. A scavenger peptide prevents methylglyoxal induced pain in mice. Biochim Biophys Acta Mol Basis Dis 2017; 1863 (03) 654-662
43 Jones RG, Pearce EJ. MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity 2017; 46 (05) 730-742
44 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149 (02) 274-293
45 Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009; 10 (05) 307-318
46 Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol 2015; 15 (10) 599-614
47 Arthur JSC, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013; 13 (09) 679-692
48 Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab 2012; 15 (04) 432-437
49 Van den Bossche J, O'Neill LAJ, Menon D. Macrophage immunometabolism: Where are we (going)?. Trends Immunol 2017; 38 (06) 395-406
50 Amiel E, Everts B, Fritz D. et al. Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J Immunol 2014; 193 (06) 2821-2830
51 Krawczyk CM, Holowka T, Sun J. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115 (23) 4742-4749
52 Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 2017; 356 (6337): 513-519
53 Everts B, Amiel E, Huang SCC. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nat Immunol 2014; 15 (04) 323-332
54 Ieronymaki E, Theodorakis EM, Lyroni K. et al. Insulin resistance in macrophages alters their metabolism and promotes an M2-like phenotype. J Immunol 2019; 202 (06) 1786-1797
55 Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444 (7121): 881-887
56 Yang Q, Vijayakumar A, Kahn BB. Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol 2018; 19 (10) 654-672
57 Thornalley PJ, Hooper NI, Jennings PE. et al. The human red blood cell glyoxalase system in diabetes mellitus. Diabetes Res Clin Pract 1989; 7 (02) 115-120
58 Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol 2005; 3 (01) 36-46
59 Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454 (7203): 428-435
60 Fan X, Subramaniam R, Weiss MF, Monnier VM. Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. Arch Biochem Biophys 2003; 409 (02) 274-286
61 Rachman H, Kim N, Ulrichs T. et al. Critical role of methylglyoxal and AGE in mycobacteria-induced macrophage apoptosis and activation. PLoS One 2006; 1 (01) e29
62 Schuetz P, Castro P, Shapiro NI. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care 2011; 34 (03) 771-778
63 Uhle F, Weiterer S, Siegler BH, Brenner T, Lichtenstern C, Weigand MA. Advanced glycation endproducts induce self- and cross-tolerance in monocytes. Inflamm Res 2017; 66 (11) 961-968
64 Kitaura A, Nishinaka T, Hamasaki S. et al. Advanced glycation end-products reduce lipopolysaccharide uptake by macrophages. PLoS One 2021; 16 (01) e0245957
65 Laroui H, Viennois E, Xiao B. et al. Fab'-bearing siRNA TNFα-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis. J Control Release 2014; 186: 41-53
66 Veiga N, Goldsmith M, Granot Y. et al. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat Commun 2018; 9 (01) 4493

Supplementary Material

Supplementary Material

Supplementary Material