A4.3 Adipocytes Modulate the Phenotype of Macrophages through Secreted Lipids

Background Adipose tissue secretes a wide range of soluble factors that can influence whole body metabolism. Previous studies have shown an accumulation of macrophages and an enhanced pro-inflammatory profile of these cells in adipose tissue of obese mice. Modulation of macrophages by soluble mediators released by adipocytes has been proposed as a possible mechanism underlying these changes. In humans, an increased number of macrophages in adipose tissue of obese individuals have been observed, although no clear change in macrophages phenotype could be established. Moreover, no information exists about the interaction between macrophages and adipocytes in humans. Objective In the present study, we explored the possibility that adipocytes modulate the phenotype of macrophages and studied the possible molecular pathways involved in this modulation. Results Treatment of macrophages with adipocyte-conditioned medium (ACM) resulted in a strong reduction in IL-12p40 secretion upon LPS stimulation, whereas TNFα and other cytokines remained largely unaffected. This effect was independent of the source of ACM. Interestingly, the inhibition increased with increase in Body Mass Index (BMI) of the adipocyte donor. Therefore, it was hypothesised that the effect is mediated by a soluble factor whose release is correlated to the BMI of the adipocyte donor. To this end, we measured several cytokines, adipokines and lipids present in ACM. Among these, the release of several free fatty acids (FA) and PGE2 correlated with the BMI of the adipocyte donor. Further tests indicated that oleic and linoleic acid, as well as PGE2 were able to inhibit IL12p40 secretion, whereas palmitic acid could not. Upon separation of ACM protein and lipid fractions, we confirmed that inhibition of IL12p40 resides mainly in the ACM lipid fraction. Conclusions These results provide first evidence that obesity-related changes in macrophage phenotype could be mediated by adipocytes in humans. These effects are mainly mediated through lipids released by adipocytes. Intriguingly, modulation appears different than in murine obesity, indicating that the immunomodulatory effects of obesity could be different in humans and mice.

[1]  M. Giera,et al.  Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. , 2012, Biochimica et biophysica acta.

[2]  F. Gao,et al.  Resolvin D1 and Resolvin D2 Govern Local Inflammatory Tone in Obese Fat , 2012, The Journal of Immunology.

[3]  C. Serhan,et al.  Metabolomics‐Lipidomics of Eicosanoids and Docosanoids Generated by Phagocytes , 2011, Current protocols in immunology.

[4]  P. Fischer-Posovszky,et al.  THP-1 Macrophages and SGBS Adipocytes – A New Human in vitro Model System of Inflamed Adipose Tissue , 2011, Front. Endocrin..

[5]  A. Bouloumié,et al.  Immune cells in adipose tissue: key players in metabolic disorders. , 2011, Diabetes & metabolism.

[6]  C. Lumeng,et al.  Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states , 2011, Current opinion in clinical nutrition and metabolic care.

[7]  Yunan Tang,et al.  Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese‐diabetic mice , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  P. Scherer,et al.  Adipose tissue remodeling and obesity. , 2011, The Journal of clinical investigation.

[9]  R. Curi,et al.  Molecular Mechanisms by Which Saturated Fatty Acids Modulate TNF-α Expression in Mouse Macrophage Lineage , 2011, Cell Biochemistry and Biophysics.

[10]  David Montaner,et al.  Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice , 2011, Diabetes.

[11]  R. Morita,et al.  Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance , 2011, Nature communications.

[12]  R. Toes,et al.  The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype , 2011, Annals of the rheumatic diseases.

[13]  K. Strissel,et al.  T‐Cell Recruitment and Th1 Polarization in Adipose Tissue During Diet‐Induced Obesity in C57BL/6 Mice , 2010, Obesity.

[14]  R. Zechner,et al.  Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. , 2010, The Journal of clinical investigation.

[15]  M. Al-Omran,et al.  Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. , 2010, American journal of physiology. Heart and circulatory physiology.

[16]  Liwu Li,et al.  Molecular mechanism underlying the inflammatory complication of leptin in macrophages. , 2010, Molecular immunology.

[17]  Emily K Anderson,et al.  Adipose tissue recruitment of leukocytes , 2010, Current opinion in lipidology.

[18]  G. Smyth,et al.  Pro-Inflammatory CD11c+CD206+ Adipose Tissue Macrophages Are Associated With Insulin Resistance in Human Obesity , 2010, Diabetes.

[19]  K. Walsh,et al.  Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype* , 2009, The Journal of Biological Chemistry.

[20]  T. Kadowaki,et al.  CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity , 2009, Nature Medicine.

[21]  A. Lichtenstein,et al.  In vitro fatty acid enrichment of macrophages alters inflammatory response and net cholesterol accumulation , 2009, British Journal of Nutrition.

[22]  O. Wiklund,et al.  Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. , 2009, Atherosclerosis.

[23]  S. Watkins,et al.  Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism , 2008, Cell.

[24]  A. Yoshimura,et al.  Prostaglandin E2 is a major soluble factor produced by stromal cells for preventing inflammatory cytokine production from dendritic cells. , 2008, International immunology.

[25]  Chih-Hao Lee,et al.  Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. , 2008, Cell metabolism.

[26]  M. Wegner,et al.  IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas. , 2008, Cytokine.

[27]  Charles N. Serhan,et al.  Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators , 2008, Nature Reviews Immunology.

[28]  F. Karpe,et al.  Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages , 2008, Circulation.

[29]  G. Zlabinger,et al.  Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production , 2007, International Journal of Obesity.

[30]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[31]  G. Hotamisligil,et al.  Inflammation and metabolic disorders , 2006, Nature.

[32]  T. Kadowaki,et al.  Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance* , 2006, Journal of Biological Chemistry.

[33]  G. Patterson,et al.  IL-12 p80 is an innate epithelial cell effector that mediates chronic allograft dysfunction. , 2006, American journal of respiratory and critical care medicine.

[34]  R. Kitazawa,et al.  MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. , 2006, The Journal of clinical investigation.

[35]  Shupei Wang,et al.  Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200 , 2005, Journal of Lipid Research.

[36]  T. Suganami,et al.  A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes: Role of Free Fatty Acids and Tumor Necrosis Factor α , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[37]  M. Freudenberg,et al.  IL-12 family members: differential kinetics of their TLR4-mediated induction by Salmonella enteritidis and the impact of IL-10 in bone marrow-derived macrophages. , 2005, International immunology.

[38]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[39]  A. Madan,et al.  Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. , 2004, Endocrinology.

[40]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[41]  M. Neurath,et al.  An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo , 2004, Gut.

[42]  D. Loskutoff,et al.  Monocyte chemoattractant protein 1 in obesity and insulin resistance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Rhee,et al.  Saturated Fatty Acids, but Not Unsaturated Fatty Acids, Induce the Expression of Cyclooxygenase-2 Mediated through Toll-like Receptor 4* , 2001, The Journal of Biological Chemistry.

[44]  N. Kajiwara,et al.  Interleukin 12 P40 Production by Barrier Epithelial Cells during Airway Inflammation , 2001, The Journal of experimental medicine.

[45]  V. Sánchez-Margalet,et al.  Human leptin stimulates proliferation and activation of human circulating monocytes. , 1999, Cellular immunology.

[46]  D. Salamon,et al.  Increased interleukin-12 plasma concentrations in both, insulin-dependent and non-insulin-dependent diabetes mellitus , 1998, Diabetologia.

[47]  X. Cheng,et al.  Down-regulation of IL-12, not a shift from a T helper-1 to a T helper-2 phenotype, is responsible for impaired IFN-gamma production in mammary tumor-bearing mice. , 1997, Journal of immunology.

[48]  L. Aarden,et al.  Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production , 1995, The Journal of experimental medicine.

[49]  M. Gately,et al.  Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. , 1995, Journal of immunology.

[50]  Giorgio,et al.  Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells , 1992, The Journal of experimental medicine.

[51]  S. Khader,et al.  IL-12p40: an inherently agonistic cytokine. , 2007, Trends in immunology.

[52]  A. Aljada,et al.  Inflammation: the link between insulin resistance, obesity and diabetes. , 2004, Trends in immunology.

[53]  S. Gordon.  Alternative activation of macrophages , 2003, Nature Reviews Immunology.