Characterization of Inflammatory Gene Expression and Chemotaxis of Macrophages Expressing Guanylin and Guanylyl Cyclase-C
Depending upon the environment, macrophages can show at least two different phenotypes, including the inflammatory (M1) phenotype and the anti-inflammatory (M2) phenotype. CD11c–positive M1 macrophages produce proinflammatory cytokines such as interleukin (IL) 1β, IL-6, tumor necrosis factor α, and monocyte chemoattractant protein (MCP) 1, which are linked to the development of obesity-associated insulin resistance. Recently, we showed that double-transgenic (dTg) rats overexpressing guanylin (Gn) and its receptor, guanylyl cyclase-C (GC-C), specifically in macrophages did not become obese even when fed a high-fat diet. In the present study, to characterize macrophages expressing Gn and GC-C (i.e., Gn/GC-C macrophages), we analyzed the expression of the M1 and M2 markers of peritoneal macrophages isolated from dTg and wild type (WT) rats. We also examined the chemotaxis of these macrophages after incubation with MCP-1 or fatty acids. The expression of CD11c, an M1 macrophage marker were expressed at a significantly lower level in the peritoneal macrophages of dTg rats than in those of wild-type (WT) rats. In addition, the expression of IL-1, MCP-1 and chemokine receptor 2 were expressed at a significantly lower level in the peritoneal macrophages of dTg rats than in those of WT rats. On the other hand, there were no significant differences in the expression of M2 markers such as CD206, IL10, and arginine 1 between dTg and WT rats. We also found that the chemotaxis of Gn/GC-C macrophages incubated with fatty acids significantly increases compared to the macrophages of WT rats. Our results suggest that the low levels of proinflammatory cytokines and M1 markers in Gn/GC-C macrophages at least in part contribute to the anti-obese phenotype of Gn/GC-C Tg rats. In addition, the accelerated chemotaxis of Gn/GC-C macrophages in response to fatty acids suggests that these macrophages can uniquely react to excess fatty acids.
Characterization of Inflammatory Gene Expression and Chemotaxis of Macrophages Expressing Guanylin and Guanylyl Cyclase-C, American Journal of Life Sciences. Special Issue:Biology and Medicine of Peptide and Steroid Hormones.
Vol. 3, No. 3-2,
2015, pp. 43-47.
F. Ginhoux, S. Jung, Monocytes and macrophages: developmental pathways and tissue homeostasis, Nat. Rev. Immunol. 14 (2014) 392-404.
C. Shi, E.G. Pamer, Monocyte recruitment during infection and inflammation, Nat. Rev. Immunol. 11 (2011) 762-774.
J.M. den Haan, L. Martinez-Pomares, Macrophage heterogeneity in lymphoid tissues, 35 (2013) 541-552.
S. Gordon, P.R. Taylor, Monocyte and macrophage heterogeneity, Nat. Rev. Immunol. 5 (2005) 953-964.
P.J. Murray, T.A. Wynn, Protective and pathogenic functions of macrophage subsets, Nat. Rev. Immunol. 11 (2011) 723-737.
F.O. Martinez, S. Gordon, The M1 and M2 paradigm of macrophage activation: time for reassessment, F1000Prime Rep. 6 (2014) 6-13.
D. Tugal, X. Liao, M.K. Jain, Transcriptional control of macrophage polarization, Arterioscler. Thromb. Vasc. 33 (2013) 1135-1144.
Y.C. Liu, X.B. Zou, Y.F. Chai, Y.M. Yao, Macrophage polarization in inflammatory diseases, Int. J. Biol. Sci. 10 (2014) 520-529.
A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol. 2 (2004) 677-686.
V.H. Perry, J. Teeling, Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration, Semin Immunopathol. 35 (2013) 601-612.
K. Steinwede, S. Henken, J. Bohling, R. Maus, B. Ueberberg, C. Brumshagen, E.L. Brincks, T.S. Griffith, T. Welte, U.A. Maus, TNF-related apoptosis-inducing ligand (TRAIL) exerts therapeutic efficacy for the treatment of pneumococcal pneumonia in mice, J Exp Med. 209 (2012) 1937-1952.
A. Waddell, R. Ahrens, K. Steinbrecher, B. Donovan, M.E. Rothenberg, A. Munitz, S.P. Hogan, Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C (high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11, J Immunol. 186 (2011) 5993-6003.
S. Pestka, C.D. Krause, D. Sarkar, M.R. Walter, Y. Shi, P.B. Fisher, Interleukin-10 and related cytokines and receptors, Annu. Rev. Immunol. 22 (2004) 929-979.
S.H. Wei, A. Ming-Lum, Y. Liu, D. Wallach, C.J. Ong, S.W. Chung, K.W. Moore, A.L. Mui, Proteasome-mediated proteolysis of the interleukin-10 receptor is important for signal downregulation, J. Interferon. Cytokine .Res. 26 (2006) 281-290.
V. Briken, D.M. Mosser, Editorial: switching on arginase in M2 macrophages, J. Leukoc. Biol. 90 (2011) 839-841.
M. Rath, I. Müller, P. Kropf, E.I. Closs, M. Munder, Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages, Front Immunol. 5 (2014) 532.
T. Lucas, A. Waisman, R. Ranjan, J. Roes, T. Krieg, W. Müller, A. Roers, S.A. Eming, Differential roles of macrophages in diverse phases of skin repair, J. Immunol. 184 (2010) 964-977.
P.R. Nagareddy, M. Kraakman, S.L. Masters, R.A. Stirzaker, D.J. Gorman, R.W. Grant, D. Dragoljevic, E.S. Hong, A. Abdel-Latif, S.S. Smyth, S.H. Choi, J. Korner, K.E. Bornfeldt, E.A. Fisher, V.D. Dixit, A.R. Tall, I.J. Goldberg, A.J. Murphy, Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity, Cell Metab. 19 (2014) 821-835.
S.P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, A.W. Ferrante Jr, Obesity is associated with macrophage accumulation in adipose tissue, J. Clin. Invest. 112 (2003) 1796-808.
C.N. Lumeng, J.L. Bodzin, A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J. Clin. Invest. 17 (2007) 175-84.
X. Prieur, C.Y. Mok, V.R. Velagapudi, V. Núñez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O'Rahilly, J.K. Sethi, J. Dopazo, M. Orešič, M. Ricote, A. Vidal-Puig, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes 60 (2011) 797-809.
N. Arshad, S.S. Visweswariah, The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis, FEBS Lett. 586(2012) 2835-2840.
S. Akieda-Asai, M. Sugiyama, T. Miyazawa, S. Koda, I. Okano, K. Senba, P.E. Poleni, Y. Hizukuri, A. Okamoto, K. Yamahara, E. Mutoh, F. Aoyama, A. Sawaguchi, M. Furuya, M. Miyazato, K. Kangawa, Y. Date, Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet, J. Lipid. Res. 54 (2013) 85-96.
C.D. Dumitru, J.D. Ceci, C. Tsatsanis, D. Kontoyiannis, K. Stamatakis, J.H. Lin, C. Patriotis, N.A. Jenkins, N.G. Copeland, G. Kollias, P.N. Tsichlis, TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway, Cell 103 (2000) 1071-1083.
J.Y. Huh, Y.J. Park, M. Ham, J.B. Kim, Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity, Mol Cells. 37 (2014) 365-3671.
K.A. Lê, S. Mahurkar, T.L. Alderete, R.E. Hasson, T.C. Adam, J.S. Kim, E. Beale, C. Xie, A.S. Greenberg, H. Allayee, M.I. Goran, Subcutaneous adipose tissue macrophage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-κB stress pathway, Diabetes. 60 (2011) 2802-2809.
X. Prieur, C.Y. Mok, V.R. Velagapudi, V. Núñez, L. Fuentes, D. Montaner, K. Ishikawa, A. Camacho, N. Barbarroja, S. O'Rahilly, J.K. Sethi, J. Dopazo, M. Orešič, M. Ricote, A. Vidal-Puig, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes. 60 (2011) 797-809.
S.E. Shoelson, L. Herrero, A. Naaz, Obesity, inflammation,and insulin resistance, Gastroenterology, 132 (2007) 2169-2180.
S.L. Deshmane, S. Kremlev, S. Amini, B.E. Sawaya, Monocyte chemoattractant protein-1 (MCP-1): an overview, J. Interferon. Cytokine. Res. 29 (2009) 313-326.
D. Patsouris, J.G. Neels, W. Fan, P.P. Li, M.T. Nguyen, J.M. Olefsky, Glucocorticoids and thiazolidinediones interfere with adipocyte-mediated macrophage chemotaxis and recruitment. J Biol Chem. 284 (2009) 31223-312235.
C. Yeop Han, A.Y. Kargi, M. Omer, C.K. Chan, M. Wabitsch, K.D. O'Brien, T.N. Wight, A. Chait, Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation, Diabetes 59 (2010) 386-396.
K. Takahashi, S. Mizuarai, H. Araki, S. Mashiko, A. Ishihara, A. Kanatani, H. Itadani, H. Kotani, Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice, J. Biol. Chem. 278 (2003) 46654-4660.
S. Tateya, Y. Tamori, T. Kawaguchi, H. Kanda, M. Kasuga, An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice, Endocrinology. 151 (2010) 971-979.