Abstract
Growing evidence suggests that components of the innate immune system play a crucial role in regulating metabolic homeostasis. Macrophages were the primary immune cells to be described in both the white adipose tissue and the pancreatic islets. Therein, their functions, beneficial or detrimental, are extending under steady state and in the context of obesity-induced type 2 diabetes. Other populations, including innate lymphoid cells, are emerging as key sentinels of metabolic tissues and privileged partners of macrophages. The present review will thus explore the phenotype and the role of innate immune cells in metabolic physiology and dysfunction. Discussion will tackle pending questions and future perspectives in the field of immunometabolism.
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Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, Schuppan D, Gronbaek H (2019) The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 16:145–159
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830
Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370
Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M (2013) Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 17:860–872
Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969
Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D, Singer K, DelProposto JL, Geletka LM, Muir LA, Lumeng CN (2017) Macrophage proliferation sustains adipose tissue inflammation in formerly obese mice. Diabetes 66:392–406
Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M (2014) Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19:162–171
Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505
Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T (2006) Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 281:26602–26614
Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS (2007) Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56:2242–2250
Kirk EA, Sagawa ZK, McDonald TO, O'Brien KD, Heinecke JW (2008) Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 57:1254–1261
Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57:3239–3246
Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, Lacroix-Desmazes S, Bayry J, Kaveri SV, Clement K et al (2014) T cell-derived IL-22 amplifies IL-1beta-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes 63:1966–1977
Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309
Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, Landerholm RW, Crouthamel M, Gozal D, Hwang S, Singh PK, Becker L (2014) Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20:614–625
Boutens L, Hooiveld GJ, Dhingra S, Cramer RA, Netea MG, Stienstra R (2018) Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses. Diabetologia 61:942–953
Li P, Lu M, Nguyen MT, Bae EJ, Chapman J, Feng D, Hawkins M, Pessin JE, Sears DD, Nguyen AK et al (2010) Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J Biol Chem 285:15333–15345
Aouadi M, Vangala P, Yawe JC, Tencerova M, Nicoloro SM, Cohen JL, Shen Y, Czech MP (2014) Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance. Am J Physiol Endocrinol Metab 307:E374–E383
Prieur X, Mok CY, Velagapudi VR, Nunez V, Fuentes L, Montaner D, Ishikawa K, Camacho A, Barbarroja N, O'Rahilly S et al (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60:797–809
Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW Jr (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18:816–830
Huang SC, Everts B, Ivanova Y, O'Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O'Neill CM et al (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15:846–855
Shin KC, Hwang I, Choe SS, Park J, Ji Y, Kim JI, Lee GY, Choi SH, Ching J, Kovalik JP, Kim JB (2017) Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation. Nat Commun 8:1087
Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA (2018) Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci U S A 115:E5096–E5105
Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG et al (2015) Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med 21:610–618
Bourlier V, Zakaroff-Girard A, Miranville A, De Barros S, Maumus M, Sengenes C, Galitzky J, Lafontan M, Karpe F, Frayn KN et al (2008) Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation 117:806–815
Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Gyori G, Zlabinger GJ, Stulnig TM (2007) Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes 31:1420–1428
Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K (2009) Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 94:4619–4623
Dalmas E, Lehmann FM, Dror E, Wueest S, Thienel C, Borsigova M, Stawiski M, Traunecker E, Lucchini FC, Dapito DH, Kallert SM, Guigas B, Pattou F, Kerr-Conte J, Maechler P, Girard JP, Konrad D, Wolfrum C, Böni-Schnetzler M, Finke D, Donath MY (2017) Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47:928–942 e927
Calderon B, Carrero JA, Ferris ST, Sojka DK, Moore L, Epelman S, Murphy KM, Yokoyama WM, Randolph GJ, Unanue ER (2015) The pancreas anatomy conditions the origin and properties of resident macrophages. J Exp Med 212:1497–1512
Banaei-Bouchareb L, Gouon-Evans V, Samara-Boustani D, Castellotti MC, Czernichow P, Pollard JW, Polak M (2004) Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J Leukoc Biol 76:359–367
Carrero JA, McCarthy DP, Ferris ST, Wan X, Hu H, Zinselmeyer BH, Vomund AN, Unanue ER (2017) Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice. Proc Natl Acad Sci U S A 114:E10418–E10427
Boni-Schnetzler M, Boller S, Debray S, Bouzakri K, Meier DT, Prazak R, Kerr-Conte J, Pattou F, Ehses JA, Schuit FC et al (2009) Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150:5218–5229
Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F, Yagi N, Ohto U, Kimoto M, Miyake K, Tobe K, Arai H, Kadowaki T, Nagai R (2012) Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab 15:518–533
Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T et al (2014) Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med 20:1417–1426
Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhyay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G (2013) Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med 19:1132–1140
Nackiewicz D, Dan M, He W, Kim R, Salmi A, Rutti S, Westwell-Roper C, Cunningham A, Speck M, Schuster-Klein C et al (2014) TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6. Diabetologia 57:1645–1654
Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860
Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG (2009) Islet-associated macrophages in type 2 diabetes. Diabetologia 52:1686–1688
Ying W, Lee YS, Dong Y, Seidman JS, Yang M, Isaac R, Seo JB, Yang BH, Wollam J, Riopel M, McNelis J, Glass CK, Olefsky JM, Fu W (2019) Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab 29:457–474.e455
Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, Picelli S, Sabirsh A, Clausen M, Bjursell MK et al (2016) Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 24:593–607
Mahdi T, Hanzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, Axelsson AS, Zhou Y, Jing X, Almgren P et al (2012) Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes. Cell Metab 16:625–633
Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie ANJ, Mebius RE et al (2018) Innate lymphoid cells: 10 years on. Cell 174:1054–1066
Wensveen FM, Jelencic V, Valentic S, Sestan M, Wensveen TT, Theurich S, Glasner A, Mendrila D, Stimac D, Wunderlich FT et al (2015) NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol 16:376–385
Lee BC, Kim MS, Pae M, Yamamoto Y, Eberle D, Shimada T, Kamei N, Park HS, Sasorith S, Woo JR et al (2016) Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 23:685–698
O'Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P, Adams NM, Walzer T, Dannenberg AJ, Sun JC (2016) Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45:428–441
Boulenouar S, Michelet X, Duquette D, Alvarez D, Hogan AE, Dold C, O'Connor D, Stutte S, Tavakkoli A, Winters D et al (2017) Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity 46:273–286
Theurich S, Tsaousidou E, Hanssen R, Lempradl AM, Mauer J, Timper K, Schilbach K, Folz-Donahue K, Heilinger C, Sexl V, Pospisilik JA, Wunderlich FT, Brüning JC (2017) IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab 26:171–184.e176
O'Rourke RW, Meyer KA, Neeley CK, Gaston GD, Sekhri P, Szumowski M, Zamarron B, Lumeng CN, Marks DL (2014) Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring) 22:2109–2114
Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535–549
Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D (2015) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242–246
Cayrol C, Girard JP (2018) Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 281:154–168
Molofsky AB, Van Gool F, Liang HE, Van Dyken SJ, Nussbaum JC, Lee J, Bluestone JA, Locksley RM (2015) Interleukin-33 and interferon-gamma counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43:161–174
Oldenhove G, Boucquey E, Taquin A, Acolty V, Bonetti L, Ryffel B, Le Bert M, Englebert K, Boon L, Moser M (2018) PD-1 is involved in the dysregulation of type 2 innate lymphoid cells in a murine model of obesity. Cell Rep 25:2053–2060.e4
Ohne Y, Silver JS, Thompson-Snipes L, Collet MA, Blanck JP, Cantarel BL, Copenhaver AM, Humbles AA, Liu YJ (2016) IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat Immunol 17:646–655
Hams E, Bermingham R, Wurlod FA, Hogan AE, O'Shea D, Preston RJ, Rodewald HR, McKenzie AN, Fallon PG (2016) The helminth T2 RNase omega1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism. FASEB J 30:824–835
Hussaarts L, Garcia-Tardon N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, Ozir-Fazalalikhan A, Berbee JF (2015) Willems van Dijk K, van Harmelen V, et al.: Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J 29:3027–3039
Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:243–247
Kumar D, Pandya SK, Varshney S, Shankar K, Rajan S, Srivastava A, Gupta A, Gupta S, Vishwakarma AL, Misra A, Gaikwad AN (2018) Temporal immmunometabolic profiling of adipose tissue in HFD-induced obesity: manifestations of mast cells in fibrosis and senescence. Int J Obes. https://doi.org/10.1038/s41366-018-0228-5
Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM (2012) Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 18:1407–1412
Elgazar-Carmon V, Rudich A, Hadad N, Levy R (2008) Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 49:1894–1903
Zhang J, Shi GP (1822) Mast cells and metabolic syndrome. Biochim Biophys Acta 2012:14–20
Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–1128
Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE, DelProposto JB, Geletka L, Meyer KA, O'Rourke RW, Lumeng CN (2016) Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J Immunol 197:3650–3661
Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumie A, Gual P, Wakkach A (2012) Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61:2238–2247
Macdougall CE, Wood EG, Loschko J, Scagliotti V, Cassidy FC, Robinson ME, Feldhahn N, Castellano L, Voisin MB, Marelli-Berg F, Gaston-Massuet C, Charalambous M, Longhi MP (2018) Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 27:588–601.e4
Eguchi J, Kong X, Tenta M, Wang X, Kang S, Rosen ED (2013) Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. Diabetes 62:3394–3403
Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, Flask CA, Kim J, Doreian BW, Lu KQ, Kaestner KH, Hamik A, Clément K, Jain MK (2011) Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest 121:2736–2749
Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, Yoshioka Y, Morii E, Takakura N, Takeuchi O, Akira S (2013) Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 495:524–528
Nawaz A, Aminuddin A, Kado T, Takikawa A, Yamamoto S, Tsuneyama K, Igarashi Y, Ikutani M, Nishida Y, Nagai Y, Takatsu K, Imura J, Sasahara M, Okazaki Y, Ueki K, Okamura T, Tokuyama K, Ando A, Matsumoto M, Mori H, Nakagawa T, Kobayashi N, Saeki K, Usui I, Fujisaka S, Tobe K (2017) CD206(+) M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors. Nat Commun 8:286
Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263
Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74–87
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355
Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:2910–2918
Muir LA, Kiridena S, Griffin C, DelProposto JB, Geletka L, Martinez-Santibanez G, Zamarron BF, Lucas H, Singer K, O'Rourke RW et al (2018) Frontline science: rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages. J Leukoc Biol 103:615–628
Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC, Peris E, Cui C, Hoffman A, Zhou G, Fernandez S, Zhai L, Hall BA, Haka AS, Shah AM, Reardon CA, Brady MJ, Rhodes CJ, Maxfield FR, Becker L (2017) Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep 20:3149–3161
Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, Ferrante AW Jr (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120:3466–3479
Fischer-Posovszky P, Wang QA, Asterholm IW, Rutkowski JM, Scherer PE (2011) Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. Endocrinology 152:3074–3081
Stienstra R, Dijk W, van Beek L, Jansen H, Heemskerk M, Houtkooper RH, Denis S, van Harmelen V, Willems van Dijk K, Tack CJ, Kersten S (2014) Mannose-binding lectin is required for the effective clearance of apoptotic cells by adipose tissue macrophages during obesity. Diabetes 63:4143–4153
Grijalva A, Xu X, Ferrante AW Jr (2016) Autophagy is dispensable for macrophage-mediated lipid homeostasis in adipose tissue. Diabetes 65:967–980
Haka AS, Barbosa-Lorenzi VC, Lee HJ, Falcone DJ, Hudis CA, Dannenberg AJ, Maxfield FR (2016) Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation. J Lipid Res 57:980–992
Wilson AM, Shao Z, Grenier V, Mawambo G, Daudelin JF, Dejda A, Pilon F, Popovic N, Boulet S, Parinot C, Oubaha M, Labrecque N, de Guire V, Laplante M, Lettre G, Sennlaub F, Joyal JS, Meunier M, Sapieha P (2018) Neuropilin-1 expression in adipose tissue macrophages protects against obesity and metabolic syndrome. Sci Immunol 3:eaan4626
Corvera S, Gealekman O (1842) Adipose tissue angiogenesis: impact on obesity and type-2 diabetes. Biochim Biophys Acta 2014:463–472
Xu F, Burk D, Gao Z, Yin J, Zhang X, Weng J, Ye J (2012) Angiogenic deficiency and adipose tissue dysfunction are associated with macrophage malfunction in SIRT1−/− mice. Endocrinology 153:1706–1716
Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY (2007) Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 100:e47–e57
Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J (2008) Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab 295:E313–E322
Feng B, Jiao P, Nie Y, Kim T, Jun D, van Rooijen N, Yang Z, Xu H (2011) Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice. PLoS One 6:e24358
Lee YS, Li P, Huh JY, Hwang IJ, Lu M, Kim JI, Ham M, Talukdar S, Chen A, Lu WJ, Bandyopadhyay GK, Schwendener R, Olefsky J, Kim JB (2011) Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 60:2474–2483
Aouadi M, Tencerova M, Vangala P, Yawe JC, Nicoloro SM, Amano SU, Cohen JL, Czech MP (2013) Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci U S A 110:8278–8283
Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, Ofrecio JM, Wollam J, Hernandez-Carretero A, Fu W, Li P, Olefsky JM (2017) Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171:372–384.e12
Ferris ST, Zakharov PN, Wan X, Calderon B, Artyomov MN, Unanue ER, Carrero JA (2017) The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. J Exp Med 214:2369–2385
Zinselmeyer BH, Vomund AN, Saunders BT, Johnson MW, Carrero JA, Unanue ER (2018) The resident macrophages in murine pancreatic islets are constantly probing their local environment, capturing beta cell granules and blood particles. Diabetologia 61:1374–1383
Weitz JR, Makhmutova M, Almaca J, Stertmann J, Aamodt K, Brissova M, Speier S, Rodriguez-Diaz R, Caicedo A (2018) Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. Diabetologia 61:182–192
Hajmrle C, Smith N, Spigelman AF, Dai X, Senior L, Bautista A, Ferdaoussi M, MacDonald PE (2016) Interleukin-1 signaling contributes to acute islet compensation. JCI Insight 1:e86055
Zawalich WS, Zawalich KC (1989) Interleukin 1 is a potent stimulator of islet insulin secretion and phosphoinositide hydrolysis. Am J Phys 256:E19–E24
Benner C, van der Meulen T, Caceres E, Tigyi K, Donaldson CJ, Huising MO (2014) The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15:620
Burke SJ, Batdorf HM, Burk DH, Martin TM, Mendoza T, Stadler K, Alami W, Karlstad MD, Robson MJ, Blakely RD, Mynatt RL, Collier JJ (2018) Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet beta-cell de-differentiation. Mol Metab 14:95–107
Dror E, Dalmas E, Meier DT, Wueest S, Thevenet J, Thienel C, Timper K, Nordmann TM, Traub S, Schulze F et al (2017) Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 18:283–292
Boni-Schnetzler M, Hauselmann SP, Dalmas E, Meier DT, Thienel C, Traub S, Schulze F, Steiger L, Dror E, Martin P et al (2018) Beta cell-specific deletion of the IL-1 receptor antagonist impairs beta cell proliferation and insulin secretion. Cell Rep 22:1774–1786
Aguayo-Mazzucato C, Bonner-Weir S (2018) Pancreatic beta cell regeneration as a possible therapy for diabetes. Cell Metab 27:57–67
Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong JY, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC (2014) Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes beta cell regeneration. Cell Metab 19:498–511
Criscimanna A, Coudriet GM, Gittes GK, Piganelli JD, Esni F (2014) Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and beta-cell regeneration in mice. Gastroenterology 147:1106–1118.e11
Riley KG, Pasek RC, Maulis MF, Dunn JC, Bolus WR, Kendall PL, Hasty AH, Gannon M (2015) Macrophages are essential for CTGF-mediated adult beta-cell proliferation after injury. Mol Metab 4:584–591
Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, Song Z, El-Gohary Y, Prasadan K, Shiota C et al (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A 111:E1211–E1220
Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356:1517–1526
Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, Group CT (2018) Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391:319–328
Wan X, Zinselmeyer BH, Zakharov PN, Vomund AN, Taniguchi R, Santambrogio L, Anderson MS, Lichti CF, Unanue ER (2018) Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature 560:107–111
Hams E, Locksley RM, McKenzie AN, Fallon PG (2013) Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J Immunol 191:5349–5353
Ji Y, Sun S, Xia S, Yang L, Li X, Qi L (2012) Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem 287:24378–24386
Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC, Clement N, Moes S, Colombi M, Meier JA, Swierczynska MM, Jenö P, Beglinger C, Peterli R, Hall MN (2018) Insulin resistance causes inflammation in adipose tissue. J Clin Invest 128:1538–1550
Pedersen DJ, Guilherme A, Danai LV, Heyda L, Matevossian A, Cohen J, Nicoloro SM, Straubhaar J, Noh HL, Jung D, Kim JK, Czech MP (2015) A major role of insulin in promoting obesity-associated adipose tissue inflammation. Mol Metab 4:507–518
Christ A, Gunther P, Lauterbach MAR, Duewell P, Biswas D, Pelka K, Scholz CJ, Oosting M, Haendler K, Bassler K et al (2018) Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172:162–175.e14
Mourits VP, Wijkmans JC, Joosten LA, Netea MG (2018) Trained immunity as a novel therapeutic strategy. Curr Opin Pharmacol 41:52–58
Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV, Scherer PE (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 20:103–118
Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sanchez NM, Mahu I, Mendes R, Gres V, Kubasova N, Morris I et al (2017) Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med 23:1309–1318
Acknowledgements
This work was supported by the European Foundation for the Study of Diabetes (EFSD) Research Programme, the French Society for Diabetes (SFD), and the ATIP-Avenir Programme.
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This article is a contribution to the special issue on Inflammation and Type 2 Diabetes - Guest Editor: Marc Y. Donath
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Dalmas, E. Role of innate immune cells in metabolism: from physiology to type 2 diabetes. Semin Immunopathol 41, 531–545 (2019). https://doi.org/10.1007/s00281-019-00736-5
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DOI: https://doi.org/10.1007/s00281-019-00736-5