The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

Jindrich Chmelar; Kyoung-Jin Chung; Triantafyllos Chavakis

doi:10.1160/TH12-09-0703

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(03): 399-406
DOI: 10.1160/TH12-09-0703

Theme Issue Article

Schattauer GmbH

The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

Jindrich Chmelar^*

¹Division on Vascular Inflammation, Diabetes and Kidney, Department of Medicine, University Clinic Carl-Gustav-Carus, Technical University Dresden, Dresden, Germany

²Institute of Parasitology, Biology Centre, ASCR, Ceske Budejovice, Czech Republic

,

Kyoung-Jin Chung^*

¹Division on Vascular Inflammation, Diabetes and Kidney, Department of Medicine, University Clinic Carl-Gustav-Carus, Technical University Dresden, Dresden, Germany

,

Triantafyllos Chavakis

¹Division on Vascular Inflammation, Diabetes and Kidney, Department of Medicine, University Clinic Carl-Gustav-Carus, Technical University Dresden, Dresden, Germany

› Author Affiliations

Abstract

Summary

Obesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.

Keywords

Obesity - adipose tissue - inflammation - review - leukocytes

Full Text

References

References
1 Gustafson B. Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb 2010; 17: 332-341.
2 Gustafson B, Hammarstedt A, Andersson CX. et al. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27: 2276-2283.
3 Cornier MA, Dabelea D, Hernandez TL. et al. The metabolic syndrome. Endocr Rev 2008; 29: 777-822.
4 Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011; 11: 738-749.
5 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107.
6 Yudkin JS, Stehouwer CD, Emeis JJ. et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol 1999; 19: 972-978.
7 Despres JP, Lemieux I, Bergeron J. et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008; 28: 1039-1049.
8 Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140: 900-917.
9 Hoene M, Weigert C. The role of interleukin-6 in insulin resistance, body fat distribution and energy balance. Obes Rev 2008; 9: 20-29.
10 Uysal KT, Wiesbrock SM, Marino MW. et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389: 610-614.
11 Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med 1999; 245: 621-625.
12 Chatzigeorgiou A, Karalis KP, Bornstein SR. et al. Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia 2012; 55: 2583-2592.
13 Elgazar-Carmon V, Rudich A, Hadad N. et al. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 2008; 49: 1894-1903.
14 Liu J, Divoux A, Sun J. et al. Genetic deficiency and pharmacological stabilisation of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 2009; 15: 940-945.
15 Talukdar S, Oh DY, Bandyopadhyay G. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012; epub ahead of print
16 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808.
17 van Oostrom AJ, Rabelink TJ, Verseyden C. et al. Activation of leukocytes by postprandial lipemia in healthy volunteers. Atherosclerosis 2004; 177: 175-182.
18 Mohanty P, Hamouda W, Garg R. et al. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 2000; 85: 2970-2973.
19 Wentworth JM, Naselli G, Brown WA. et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010; 59: 1648-1656.
20 Winer S, Chan Y, Paltser G. et al. Normalisation of obesity-associated insulin resistance through immunotherapy. Nat Med 2009; 15: 921-929.
21 Feuerer M, Herrero L, Cipolletta D. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930-939.
22 Nishimura S, Manabe I, Nagasaki M. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914-920.
23 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-964.
24 Xu H, Barnes GT, Yang Q. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830.
25 Chen A, Mumick S, Zhang C. et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 2005; 13: 1311-1320.
26 Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarisation. J Clin Invest 2007; 117: 175-184.
27 Lumeng CN, DelProposto JB, Westcott DJ. et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008; 57: 3239-3246.
28 Westcott DJ, Delproposto JB, Geletka LM. et al. MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. J Exp Med 2009; 206: 3143-3156.
29 Lumeng CN, Deyoung SM, Saltiel AR. Macrophages block insulin action in adipocytes by altering expression of signalling and glucose transport proteins. Am J Physiol Endocrinol Metab 2007; 292: E166-174.
30 Shaul ME, Bennett G, Strissel KJ. et al. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice. Diabetes 2010; 59: 1171-1181.
31 Patsouris D, Li PP, Thapar D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008; 8: 301-309.
32 Shi H, Kokoeva MV, Inouye K. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116: 3015-3025.
33 Saberi M, Woods NB, de Luca C. et al. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 2009; 10: 419-429.
34 Pal D, Dasgupta S, Kundu R. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012; epub ahead of print
35 Kang K, Reilly SM, Karabacak V. et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarisation and insulin sensitivity. Cell Metab 2008; 7: 485-495.
36 Liao X, Sharma N, Kapadia F. et al. Kruppel-like factor 4 regulates macrophage polarisation. J Clin Invest 2011; 121: 2736-2749.
37 Nguyen KD, Qiu Y, Cui X. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011; 480: 104-108.
38 Kanda H, Tateya S, Tamori Y. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505.
39 Weisberg SP, Hunter D, Huber R. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115-124.
40 Kirk EA, Sagawa ZK, McDonald TO. et al. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 2008; 57: 1254-1261.
41 Inouye KE, Shi H, Howard JK. et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007; 56: 2242-2250.
42 Feral CC, Neels JG, Kummer C. et al. Blockade of alpha4 integrin signalling ameliorates the metabolic consequences of high-fat diet-induced obesity. Diabetes 2008; 57: 1842-1851.
43 Kawano Y, Nakae J, Watanabe N. et al. Loss of Pdk1-Foxo1 signalling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. Diabetes 2012; 61: 1935-1948.
44 Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity 2007; 26: 741-750.
45 Dominguez PM, Ardavin C. Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation. Immunol Rev 2011; 234: 90-104.
46 Musilli C, Paccosi S, Pala L. et al. Characterisation of circulating and monocyte-derived dendritic cells in obese and diabetic patients. Mol Immunol 2011; 49: 234-238.
47 Bertola A, Ciucci T, Rousseau D. et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 2012; 61: 2238-2247.
48 Stefanovic-Racic M, Yang X, Turner MS. et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 2012; 61: 2330-2339.
49 Zhong J, Rao X, Deiuliis J. et al. A Potential Role for Dendritic Cell/Macrophage-Expressing DPP4 in Obesity-Induced Visceral Inflammation. Diabetes. 2012; epub ahead of print
50 Yekollu SK, Thomas R, O’Sullivan B. Targeting curcusomes to inflammatory dendritic cells inhibits NF-kappaB and improves insulin resistance in obese mice. Diabetes 2012; 60: 2928-2938.
51 Soehnlein O, Zernecke A, Eriksson EE. et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 2008; 112: 1461-1471.
52 Gerhardt CC, Romero IA, Cancello R. et al. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001; 175: 81-92.
53 Andrade VL, Petruceli E, Belo VA. et al. Evaluation of plasmatic MMP-8, MMP-9, TIMP-1 and MPO levels in obese and lean women. Clin Biochem 2012; 45: 412-415.
54 Houghton AM, Rzymkiewicz DM, Ji H. et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 2010; 16: 219-223.
55 Cai TQ, Wright SD. Human leukocyte elastase is an endogenous ligand for the integrin CR3 (CD11b/CD18, Mac-1, alpha M beta 2) and modulates polymorphonuclear leukocyte adhesion. J Exp Med 1996; 184: 1213-1223.
56 Soehnlein O, Weber C, Lindbom L. Neutrophil granule proteins tune monocytic cell function. Trends Immunol 2009; 30: 538-546.
57 Korkmaz B, Horwitz MS, Jenne DE. et al. Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 2010; 62: 726-759.
58 Yvan-Charvet L, Welch C, Pagler TA. et al. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signalling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 2008; 118: 1837-1847.
59 Drechsler M, Megens RT, van Zandvoort M. et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122: 1837-1845.
60 Viardot A, Heilbronn LK, Samocha-Bonet D. et al. Obesity is associated with activated and insulin resistant immune cells. Diabetes Metab Res Rev 2012; 28: 447-454.
61 Kordonowy LL, Burg E, Lenox CC. et al. Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. Am J Respir Cell Mol Biol 2012; 47: 120-127.
62 Hu N, Westra J, Rutgers A. et al. Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration. Arthritis Res Ther 2011; 13: R201.
63 Trellakis S, Rydleuskaya A, Fischer C. et al. Low adiponectin, high levels of apoptosis and increased peripheral blood neutrophil activity in healthy obese subjects. Obes Facts 2012; 5: 305-318.
64 Wu D, Molofsky AB, Liang HE. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011; 332: 243-247.
65 Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI. et al. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci USA 2010; 107: 22617-22622.
66 Ji Y, Sun S, Xia S. et al. Short term high fat diet challenge promotes alternative macrophage polarisation in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem 2012; 287: 24378-24386.
67 Ji Y, Sun S, Xu A. et al. Activation of natural killer T cells promotes M2 Macrophage polarisation in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signalling axis in obesity. J Biol Chem 2012; 287: 13561-13571.
68 Calixto MC, Lintomen L, Schenka A. et al. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. Br J Pharmacol 2010; 159: 617-625.
69 Kato H, Ueki S, Kamada R. et al. Leptin has a priming effect on eotaxin-induced human eosinophil chemotaxis. Int Arch Allergy Immunol 2011; 155: 335-344.
70 Vieira VJ, Ronan AM, Windt MR. et al. Elevated atopy in healthy obese women. Am J Clin Nutr 2005; 82: 504-509.
71 Maizels RM, Allen JE. Immunology. Eosinophils forestall obesity. Science 2011; 332: 186-187.
72 Gri G, Frossi B, D’Inca F. et al. Mast cell: an emerging partner in immune interaction. Front Immunol 2012; 3: 120.
73 Otsuka A, Kubo M, Honda T. et al. Requirement of interaction between mast cells and skin dendritic cells to establish contact hypersensitivity. PLoS One 2011; 6: e25538.
74 Irani AA, Schechter NM, Craig SS. et al. Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 1986; 83: 4464-4468.
75 Xu JM, Shi GP. Emerging role of mast cells and macrophages in cardiovascular and metabolic diseases. Endocr Rev 2012; 33: 71-108.
76 Altintas MM, Azad A, Nayer B. et al. Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 2011; 52: 480-488.
77 Altintas MM, Nayer B, Walford EC. et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids Health Dis 2012; 11: 21.
78 Altintas MM, Rossetti MA, Nayer B. et al. Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice. Lipids Health Dis 2011; 10: 198.
79 Rodewald HR, Feyerabend TB. Widespread immunological functions of mast cells: fact or fiction?. Immunity 2012; 37: 13-24.
80 Dudeck A, Dudeck J, Scholten J. et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 2012; 34: 973-984.
81 Feyerabend TB, Weiser A, Tietz A. et al. Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 2011; 35: 832-844.
82 Tanaka A, Nomura Y, Matsuda A. et al. Mast cells function as an alternative modulator of adipogenesis through 15-deoxy-delta-12, 14-prostaglandin J2. Am J Physiol Cell Physiol 2011; 301: C1360-1367.
83 Tsuruda T, Kato J, Hatakeyama K. et al. Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ Res 2008; 102: 1368-1377.
84 Triggiani M, Granata F, Frattini A. et al. Activation of human inflammatory cells by secreted phospholipases A2. Biochim Biophys Acta 2006; 1761: 1289-1300.
85 Company C, Piqueras L, Naim Abu Nabah Y. et al. Contributions of ACE and mast cell chymase to endogenous angiotensin II generation and leucocyte recruitment in vivo. Cardiovasc Res 2011; 92: 48-56.
86 Di Santo JP. Natural killer cell developmental pathways: a question of balance. Annu Rev Immunol 2006; 24: 257-286.
87 Malhotra A, Shanker A. NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011; 3: 1143-1166.
88 Costantini C, Cassatella MA. The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity. J Leukoc Biol 2011; 89: 221-233.
89 Nieman DC, Henson DA, Nehlsen-Cannarella SL. et al. Influence of obesity on immune function. J Am Diet Assoc 1999; 99: 294-299.
90 Scanga CB, Verde TJ, Paolone AM. et al. Effects of weight loss and exercise training on natural killer cell activity in obese women. Med Sci Sports Exerc 1998; 30: 1666-1671.
91 Guo H, Xu B, Gao L. et al. High frequency of activated natural killer and natural killer T-cells in patients with new onset of type 2 diabetes mellitus. Exp Biol Med (Maywood) 2012; 237: 556-562.
92 Lynch LA, O’Connell JM, Kwasnik AK. et al. Are natural killer cells protecting the metabolically healthy obese patient?. Obesity 2009; 17: 601-605.
93 Kelley DS, Daudu PA, Branch LB. et al. Energy restriction decreases number of circulating natural killer cells and serum levels of immunoglobulins in overweight women. Eur J Clin Nutr 1994; 48: 9-18.
94 Duffaut C, Galitzky J, Lafontan M. et al. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun 2009; 384: 482-485.
95 Barra NG, Chew MV, Reid S. et al. Interleukin-15 treatment induces weight loss independent of lymphocytes. PLoS One 2012; 7: e39553.
96 Barra NG, Reid S, MacKenzie R. et al. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity 2010; 18: 1601-1607.
97 Tian Z, Sun R, Wei H. et al. Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochem Biophys Res Commun 2002; 298: 297-302.
98 Wrann CD, Laue T, Hubner L. et al. Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions. Am J Physiol Endocrinol Metab 2011; 302: E108-116.
99 Nave H, Mueller G, Siegmund B. et al. Resistance of Janus kinase-2 dependent leptin signalling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology 2008; 149: 3370-3378.
100 Hayakawa Y, Smyth MJ. Innate immune recognition and suppression of tumors. Adv Cancer Res 2006; 95: 293-322.
101 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832.
102 Stienstra R, Joosten LA, Koenen T. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010; 12: 593-605.
103 Wen H, Gris D, Lei Y. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signalling. Nat Immunol 2011; 12: 408-415.
104 Vandanmagsar B, Youm YH, Ravussin A. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011; 17: 179-188.