Skip to main content
SpringerLink
Log in

Serotonin Modulation of Macrophage Polarization: Inflammation and Beyond

  • Chapter
  • First Online:
Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 824))

Abstract

Macrophages display a ample plethora of effector functions whose acquisition is promoted by the surrounding cytokine and cellular environment. Depending on the stimulus, macrophages become specialized (“polarized”) for either pathogen elimination, tissue repair and wound healing or immunosuppression. This “polarization” versatility allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiological agent of chronic inflammation, autoimmune diseases, cancer and even obesity and insulin resistance. In the present review we describe current concepts on the molecular basis and the patho-physiological implications of macrophage polarization, and describe its modulation by serotonin (5-HT), a neurotransmitter that regulates inflammation and tissue repair via a large set of receptors (5-HTR1-7). 5-HT modulates the phenotypic and functional polarization of macrophages, and contributes to the maintenance of an anti-inflammatory state mainly via 5-HTR2B and 5-HTR7, whose activation has a great impact on macrophage gene expression profile. The identification of 5-HTR2B and 5-HTR7 as functionally-relevant polarization markers suggests their therapeutic value in inflammatory pathologies as well as their potential involvement in linking the immune and nervous systems.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Karnovsky ML. Metchnikoff in Messina: a century of studies on phagocytosis. N Engl J Med. 1981;304:1178–80.

    CAS  PubMed  Google Scholar 

  2. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.

    CAS  PubMed  Google Scholar 

  3. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23:344–6.

    CAS  PubMed  Google Scholar 

  5. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    CAS  PubMed  Google Scholar 

  6. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.

    CAS  PubMed  Google Scholar 

  7. Fleetwood AJ, Dinh H, Cook AD, Hertzog PJ, Hamilton JA. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol. 2009;86:411–21.

    CAS  PubMed  Google Scholar 

  8. Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol. 2007;178:5245–52.

    CAS  PubMed  Google Scholar 

  9. Erblich B, Zhu L, Etgen AM, Dobrenis K, Pollard JW. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One. 2011;6:e26317.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Erhardt A, Biburger M, Papadopoulos T, Tiegs G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology. 2007;45:475–85.

    CAS  PubMed  Google Scholar 

  12. Ruiter DJ, van der Meulen J, Brouwer A, Hummel MJ, Mauw BJ, van der Ploeg JC, Wisse E. Uptake by liver cells of endotoxin following its intravenous injection. Lab Invest. 1981;45:38–45.

    CAS  PubMed  Google Scholar 

  13. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–86.

    CAS  PubMed  Google Scholar 

  14. Bedoret D, Wallemacq H, Marichal T, Desmet C, Quesada Calvo F, Henry E, et al. Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J Clin Invest. 2009;119:3723–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007;8:1086–94.

    CAS  PubMed  Google Scholar 

  16. Horsnell WG, Brombacher F. Genes associated with alternatively activated macrophages discretely regulate helminth infection and pathogenesis in experimental mouse models. Immunobiology. 2010;215:704–8.

    CAS  PubMed  Google Scholar 

  17. Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH, et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest. 2005;115:66–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Smith PD, Ochsenbauer-Jambor C, Smythies LE. Intestinal macrophages: unique effector cells of the innate immune system. Immunol Rev. 2005;206:149–59.

    CAS  PubMed  Google Scholar 

  19. Nemeth E, Baird AW, O’Farrelly C. Microanatomy of the liver immune system. Semin Immunopathol. 2009;31:333–43.

    PubMed  Google Scholar 

  20. Yamamoto T, Kaizu C, Kawasaki T, Hasegawa G, Umezu H, Ohashi RJ, et al. Macrophage colony-stimulating factor is indispensable for repopulation and differentiation of Kupffer cells but not for splenic red pulp macrophages in osteopetrotic (op/op) mice after macrophage depletion. Cell Tissue Res. 2008;332:245–56.

    Google Scholar 

  21. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010;207:1067–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Weinberg JB, Haney AF, Xu FJ, Ramakrishnan S. Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content. Blood. 1991;78:513–6.

    CAS  PubMed  Google Scholar 

  23. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, Beschin A, Raes G, De Baetselier P. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology. 2006;211:487–501.

    PubMed  Google Scholar 

  24. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.

    CAS  PubMed  Google Scholar 

  25. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317:666–70.

    CAS  PubMed  Google Scholar 

  26. Bystrom J, Evans I, Newson J, Stables M, Toor I, van Rooijen N, et al. Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood. 2008;112:4117–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Weigert A, Weichand B, Brune B. S1P regulation of macrophage functions in the context of cancer. Anticancer Agents Med Chem. 2011;11:818–29.

    CAS  PubMed  Google Scholar 

  29. Troidl C, Mollmann H, Nef H, Masseli F, Voss S, Szardien S, et al. Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction. J Cell Mol Med. 2009;13:3485–96.

    CAS  PubMed  Google Scholar 

  30. David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011;12:388–99.

    CAS  PubMed  Google Scholar 

  31. Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 1998;4:814–21.

    CAS  PubMed  Google Scholar 

  32. Weber MS, Prod’homme T, Youssef S, Dunn SE, Rundle CD, Lee L, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13:935–43.

    CAS  PubMed  Google Scholar 

  33. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Bourlier V, Zakaroff-Girard A, Miranville A, De Barros S, Maumus M, Sengenes C, et al. Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation. 2008;117:806–15.

    CAS  PubMed  Google Scholar 

  36. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011;121:985–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116:115–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480:104–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61.

    CAS  PubMed  Google Scholar 

  40. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. A Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, Palmqvist R. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One. 2012;7:e47045.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009;206:1327–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Chen P, Huang Y, Bong R, Ding Y, Song N, Wang X, et al. Tumor-associated macrophages promote angiogenesis and melanoma growth via adrenomedullin in a paracrine and autocrine manner. Clin Cancer Res. 2011;17:7230–9.

    CAS  PubMed  Google Scholar 

  45. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249–62.

    CAS  PubMed  Google Scholar 

  46. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96.

    CAS  PubMed  Google Scholar 

  47. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–90.

    CAS  PubMed  Google Scholar 

  48. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol. 2000;164:762–7.

    CAS  PubMed  Google Scholar 

  49. Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev. 2006;25:323–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b + peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009;284:34342–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117:1155–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.

    CAS  PubMed  Google Scholar 

  53. Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Pluddemann A, et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol. 2006;176:5023–32.

    CAS  PubMed  Google Scholar 

  54. Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 2012;33:119–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238–46.

    CAS  PubMed  Google Scholar 

  56. Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009;4:e6562.

    PubMed Central  PubMed  Google Scholar 

  57. Zheng Y, Cai Z, Wang S, Zhang X, Qian J, Hong S, et al. Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood. 2009;114:3625–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, Davis RJ. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science. 2013;339:218–22.

    CAS  PubMed  Google Scholar 

  59. Lacey DC, Achuthan A, Fleetwood AJ, Dinh H, Roiniotis J, Scholz GM, Chang MW, et al. Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J Immunol. 2012;188:5752–65.

    CAS  PubMed  Google Scholar 

  60. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.

    CAS  PubMed  Google Scholar 

  61. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol. 2011;6:275–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303–11.

    CAS  PubMed  Google Scholar 

  63. Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab. 2012;15:432–7.

    CAS  PubMed  Google Scholar 

  64. Cairo G, Recalcati S, Mantovani A, Locati M. Iron trafficking and metabolism in macrophages: contribution to the polarized phenotype. Trends Immunol. 2011;32:241–7.

    CAS  PubMed  Google Scholar 

  65. Puig-Kroger A, Sierra-Filardi E, Dominguez-Soto A, Samaniego R, Corcuera MT, Gomez-Aguado F, et al. Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. Cancer Res. 2009;69:9395–403.

    PubMed  Google Scholar 

  66. Samaniego R, Palacios BS, Domiguez-Soto A, Vidal C, Salas A, Matsuyama T, et al. Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A. J Leukoc Biol. 2014;95:797–808.

    Google Scholar 

  67. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 2012;15:813–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Bories G, Colin S, Vanhoutte J, Derudas B, Copin C, Fanchon M, et al. Liver X receptor (LXR) activation stimulates iron export in human alternative macrophages. Circ Res. 2013;113:1196–205.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Sierra-Filardi E, Vega MA, Sanchez-Mateos P, Corbi AL, Puig-Kroger A. Heme oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology. 2010;215:788–95.

    CAS  PubMed  Google Scholar 

  71. Dominguez-Soto A, Sierra-Filardi E, Puig-Kroger A, Perez-Maceda B, Gomez-Aguado F, Corcuera MT, et al. Dendritic cell-specific ICAM-3-grabbing nonintegrin expression on M2-polarized and tumor-associated macrophages is macrophage-CSF dependent and enhanced by tumor-derived IL-6 and IL-10. J Immunol. 2011;186:2192–200.

    CAS  PubMed  Google Scholar 

  72. Chaitidis P, Billett E, Kuban RJ, Ungethuem U, Kuhn H. Expression regulation of MAO isoforms in monocytic cells in response to Th2 cytokines. Med Sci Monit. 2005;11:BR259–65.

    CAS  PubMed  Google Scholar 

  73. Jaguin M, Houlbert N, Fardel O, Lecureur V. Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 2013;281:51–61.

    CAS  PubMed  Google Scholar 

  74. Ghassabeh GH, De Baetselier P, Brys L, Noel W, Van Ginderachter JA, Meerschaut S, et al. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood. 2006;108:575–83.

    CAS  PubMed  Google Scholar 

  75. Sierra-Filardi E, Puig-Kroger A, Blanco FJ, Nieto C, Bragado R, Palomero MI, et al. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood. 2011;117:5092–101.

    CAS  PubMed  Google Scholar 

  76. Escribese MM, Sierra-Filardi E, Nieto C, Samaniego R, Sanchez-Torres C, Matsuyama T, et al. The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. J Immunol. 2012;189:1946–54.

    CAS  PubMed  Google Scholar 

  77. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. TIRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011;12:231–8.

    CAS  PubMed  Google Scholar 

  78. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    CAS  PubMed  Google Scholar 

  79. Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, et al. p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006;66:11432–40.

    CAS  PubMed  Google Scholar 

  80. Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood. 2006;107:2112–22.

    CAS  PubMed  Google Scholar 

  81. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009;106:14978–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Cao S, Zhang X, Edwards JP, Mosser DM. NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. J Biol Chem. 2006;281:26041–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.

    CAS  PubMed  Google Scholar 

  84. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.

    CAS  PubMed  Google Scholar 

  85. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med. 2009;206:2027–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44.

    CAS  PubMed  Google Scholar 

  87. Spence S, Fitzsimons A, Boyd CR, Kessler J, Fitzgerald D, Elliott J, et al. Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization. Immunity. 2013;38:66–78.

    CAS  PubMed  Google Scholar 

  88. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    CAS  PubMed  Google Scholar 

  89. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, et al. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest. 2007;117:1658–69.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Szanto A, Balint BL, Nagy ZS, Barta E, Dezso B, Pap A, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity. 2010;33:699–712.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, et al. A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A. 2009;106:17475–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Liu YW, Tseng HP, Chen LC, Chen BK, Chang WC. Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein beta and delta in lipopolysaccharide-induced gene activation of IL-10 in mouse macrophages. J Immunol. 2003;171:821–8.

    CAS  PubMed  Google Scholar 

  94. Gray MJ, Poljakovic M, Kepka-Lenhart D, Morris Jr SM. Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene. 2005;353:98–106.

    CAS  PubMed  Google Scholar 

  95. Park JM, Greten FR, Wong A, Westrick RJ, Arthur JS, Otsu K, et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis–CREB and NF-kappaB as key regulators. Immunity. 2005;23:319–29.

    CAS  PubMed  Google Scholar 

  96. Banerjee S, Xie N, Cui H, Tan Z, Yang S, Icyuz M, et al. MicroRNA let-7c regulates macrophage polarization. J Immunol. 2013;190:6542–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, et al. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol. 2010;185:642–52.

    CAS  PubMed  Google Scholar 

  98. Sakai Y, Honda M, Fujinaga H, Tatsumi I, Mizukoshi E, Nakamoto Y, et al. Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Res. 2008;68:10267–79.

    CAS  PubMed  Google Scholar 

  99. Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S. Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother. 2005;54:1137–42.

    CAS  PubMed  Google Scholar 

  100. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11:1314–21.

    CAS  PubMed  Google Scholar 

  101. Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009;15:114–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Albesiano E, Davis M, See AP, Han JE, Lim M, Pardoll DM, et al. Immunologic consequences of signal transducers and activators of transcription 3 activation in human squamous cell carcinoma. Cancer Res. 2010;70:6467–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B. Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009;57:1458–67.

    PubMed  Google Scholar 

  104. Herrmann A, Kortylewski M, Kujawski M, Zhang C, Reckamp K, Armstrong B, et al. Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Res. 2010;70:7455–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 2005;65:3437–46.

    CAS  PubMed  Google Scholar 

  106. Weigert A, Tzieply N, von Knethen A, Johann AM, Schmidt H, Geisslinger G, et al. Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. Mol Biol Cell. 2007;18:3810–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Weigert A, Johann AM, von Knethen A, Schmidt H, Geisslinger G, Brune B. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood. 2006;108:1635–42.

    CAS  PubMed  Google Scholar 

  108. Bondanza A, Zimmermann VS, Rovere-Querini P, Turnay J, Dumitriu IE, Stach CM, et al. Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med. 2004;200:1157–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Cloez-Tayarani I, Changeux JP. Nicotine and serotonin in immune regulation and inflammatory processes: a perspective. J Leukoc Biol. 2007;81:599–606.

    CAS  PubMed  Google Scholar 

  110. Mossner R, Lesch KP. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun. 1998;12:249–71.

    CAS  PubMed  Google Scholar 

  111. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol. 2011;11:29–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev. 2008;108:1614–41.

    CAS  PubMed  Google Scholar 

  113. Lesurtel M, Soll C, Graf R, Clavien PA. Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. Cell Mol Life Sci. 2008;65:940–52.

    CAS  PubMed  Google Scholar 

  114. Vane JR. The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation. Br J Pharmacol Chemother. 1959;14:87–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Bradley PB, Humphrey PP, Williams RH. Evidence for the existence of 5-hydroxytryptamine receptors, which are not of the 5-HT2 type, mediating contraction of rabbit isolated basilar artery. Br J Pharmacol. 1986;87:3–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Bonhaus DW, Bach C, DeSouza A, Salazar FH, Matsuoka BD, Zuppan P, et al. The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol. 1995;115:622–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Foguet M, Hoyer D, Pardo LA, Parekh A, Kluxen FW, Kalkman HO, et al. Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J. 1992;11:3481–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Baxter GS. Novel discriminatory ligands for 5-HT2B receptors. Behav Brain Res. 1996;73:149–52.

    CAS  PubMed  Google Scholar 

  119. Choi DS, Ward SJ, Messaddeq N, Launay JM, Maroteaux L. 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development. 1997;124:1745–5.

    CAS  PubMed  Google Scholar 

  120. Nebigil CG, Etienne N, Schaerlinger B, Hickel P, Launay JM, Maroteaux L. Developmentally regulated serotonin 5-HT2B receptors. Int J Dev Neurosci. 2001;19:365–72.

    CAS  PubMed  Google Scholar 

  121. Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, et al. Ras involvement in signal transduction by the serotonin 5-HT2B receptor. J Biol Chem. 1996;271:3141–7.

    CAS  PubMed  Google Scholar 

  122. Nebigil CG, Launay JM, Hickel P, Tournois C, Maroteaux L. 5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways. Proc Natl Acad Sci U S A. 2000;97:2591–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Nebigil CG, Choi DS, Dierich A, Hickel P, Le Meur M, Messaddeq N, et al. Serotonin 2B receptor is required for heart development. Proc Natl Acad Sci U S A. 2000;97:9508–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Nebigil CG, Maroteaux L. Functional consequence of serotonin/5-HT2B receptor signaling in heart: role of mitochondria in transition between hypertrophy and heart failure? Circulation. 2003;108:902–8.

    PubMed  Google Scholar 

  125. Tharayil VS, Wouters MM, Stanich JE, Roeder JL, Lei S, Beyder A, et al. Lack of serotonin 5-HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo. Neurogastroenterol Motil. 2010;22:462–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Svejda B, Kidd M, Giovinazzo F, Eltawil K, Gustafsson BI, Pfragner R, et al. The 5-HT(2B) receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment. Cancer. 2010;116:2902–12.

    CAS  PubMed  Google Scholar 

  127. Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med. 2010;16:804–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Nebigil CG, Jaffre F, Messaddeq N, Hickel P, Monassier L, Launay JM, Maroteaux L. Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy. Circulation. 2003;107:3223–9.

    CAS  PubMed  Google Scholar 

  129. Nebigil CG, Maroteaux L. A novel role for serotonin in heart. Trends Cardiovasc Med. 2001;11:329–35.

    CAS  PubMed  Google Scholar 

  130. Baudry A, Bitard J, Mouillet-Richard S, Locker M, Poliard A, Launay JM, et al. Serotonergic 5-HT(2B) receptor controls tissue-nonspecific alkaline phosphatase activity in osteoblasts via eicosanoids and phosphatidylinositol-specific phospholipase C. J Biol Chem. 2010;285:26066–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Gunther S, Maroteaux L, Schwarzacher SW. Endogenous 5-HT2B receptor activation regulates neonatal respiratory activity in vitro. J Neurobiol. 2006;66:949–61.

    PubMed  Google Scholar 

  132. Niebert M, Vogelgesang S, Koch UR, Bischoff AM, Kron M, Bock N, et al. Expression and function of serotonin 2A and 2B receptors in the mammalian respiratory network. PLoS One. 2011;6:e21395.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581–8.

    CAS  PubMed  Google Scholar 

  134. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335:609–16.

    CAS  PubMed  Google Scholar 

  135. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–41.

    CAS  PubMed  Google Scholar 

  136. Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000;57:75–81.

    CAS  PubMed  Google Scholar 

  137. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045–66.

    PubMed Central  PubMed  Google Scholar 

  138. Launay JM, Herve P, Peoc’h K, Tournois C, Callebert J, Nebigil CG, et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med. 2002;8:1129–35.

    CAS  PubMed  Google Scholar 

  139. Esteve JM, Launay JM, Kellermann O, Maroteaux L. Functions of serotonin in hypoxic pulmonary vascular remodeling. Cell Biochem Biophys. 2007;47:33–44.

    CAS  PubMed  Google Scholar 

  140. Jahnichen S, Glusa E, Pertz H. Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs. Naunyn Schmiedebergs Arch Pharmacol. 2005;371:89–98.

    CAS  PubMed  Google Scholar 

  141. Diller GP, Thum T, Wilkins MR, Wharton J. Endothelial progenitor cells in pulmonary arterial hypertension. Trends Cardiovasc Med. 2010;20:22–9.

    CAS  PubMed  Google Scholar 

  142. Launay JM, Herve P, Callebert J, Mallat Z, Collet C, Doly S, et al. Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension. Blood. 2012;119:1772–80.

    CAS  PubMed  Google Scholar 

  143. Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, et al. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron. 1993;11:449–58.

    CAS  PubMed  Google Scholar 

  144. Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, et al. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci U S A. 1993;90:8547–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL. Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem. 1993;268:23422–6.

    CAS  PubMed  Google Scholar 

  146. Matthys A, Haegeman G, Van Craenenbroeck K, Vanhoenacker P. Role of the 5-HT7 receptor in the central nervous system: from current status to future perspectives. Mol Neurobiol. 2011;43:228–53.

    CAS  PubMed  Google Scholar 

  147. Janssen P, Prins NH, Moreaux B, Meulemans AL, Lefebvre RA. Characterization of 5-HT7-receptor-mediated gastric relaxation in conscious dogs. Am J Physiol Gastrointest Liver Physiol. 2005;289:G108–15.

    CAS  PubMed  Google Scholar 

  148. Inoue M, Kitazawa T, Cao J, Taneike T. 5-HT7 receptor-mediated relaxation of the oviduct in nonpregnant proestrus pigs. Eur J Pharmacol. 2003;461:207–18.

    CAS  PubMed  Google Scholar 

  149. Kitazawa T, Nakagoshi K, Teraoka H, Taneike T. 5-HT(7) receptor and beta(2)-adrenoceptor share in the inhibition of porcine uterine contractility in a muscle layer-dependent manner. Eur J Pharmacol. 2011;433:187–97.

    Google Scholar 

  150. Crider JY, Williams GW, Drace CD, Katoli P, Senchyna M, Sharif NA. Pharmacological characterization of a serotonin receptor (5-HT7) stimulating cAMP production in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2003;44:4837–44.

    PubMed  Google Scholar 

  151. Leopoldo M, Lacivita E, Contino M, Colabufo NA, Berardi F, Perrone R. Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. J Med Chem. 2007;50:4214–21.

    CAS  PubMed  Google Scholar 

  152. Perez-Garcia GS, Meneses A. Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task. Behav Brain Res. 2005;163:136–40.

    CAS  PubMed  Google Scholar 

  153. Norum JH, Hart K, Levy FO. Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J Biol Chem. 2003;278:3098–104.

    CAS  PubMed  Google Scholar 

  154. Lin SL, Johnson-Farley NN, Lubinsky DR, Cowen DS. Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac. J Neurochem. 2003;87:1076–85.

    CAS  PubMed  Google Scholar 

  155. Kvachnina E, Liu G, Dityatev A, Renner U, Dumuis A, Richter DW, et al. 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci. 2005;25:7821–30.

    CAS  PubMed  Google Scholar 

  156. Leon-Ponte M, Ahern GP, O’Connell PJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood. 2005;109:3139–46.

    Google Scholar 

  157. Mahe C, Loetscher E, Dev KK, Bobirnac I, Otten U, Schoeffter P. Serotonin 5-HT7 receptors coupled to induction of interleukin-6 in human microglial MC-3 cells. Neuropharmacology. 2005;49:40–7.

    CAS  PubMed  Google Scholar 

  158. Lieb K, Biersack L, Waschbisch A, Orlikowski S, Akundi RS, Candelario-Jalil R, et al. Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells. J Neurochem. 2005;93:549–59.

    CAS  PubMed  Google Scholar 

  159. Irving HR, Tan YY, Tochon-Danguy N, Liu H, Chetty N, Desmond PV, et al. Comparison of 5-HT4 and 5-HT7 receptor expression and function in the circular muscle of the human colon. Life Sci. 2007;80:1198–205.

    CAS  PubMed  Google Scholar 

  160. Svejda B, Kidd M, Timberlake A, Harry K, Kazberouk A, Schimmack S, et al. Serotonin and the 5-HT7 receptor: the link between Hepatocytes, IGF-1 and Small intestinal neuroendocrine tumors. Cancer Sci. 2013;104:844–55.

    CAS  PubMed  Google Scholar 

  161. Read KE, Sanger GJ, Ramage AG. Evidence for the involvement of central 5-HT7 receptors in the micturition reflex in anaesthetized female rats. Br J Pharmacol. 2003;140:53–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Recio P, Barahona MV, Orensanz LM, Bustamante S, Martinez AC, Benedito S, et al. 5-hydroxytryptamine induced relaxation in the pig urinary bladder neck. Br J Pharmacol. 2009;157:271–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Kim JJ, Bridle BW, Ghia JE, Wang H, Syed SN, Manocha MM. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation. J Immunol. 2013;190:4795–804.

    CAS  PubMed  Google Scholar 

  164. Guscott M, Bristow LJ, Hadingham K, Rosahl TW, Beer MS, Stanton JA, et al. Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology. 2005;48:492–502.

    CAS  PubMed  Google Scholar 

  165. Thomas DR, Melotto S, Massagrande M, Gribble AD, Jeffrey P, Stevens AJ, et al. SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats. Br J Pharmacol. 2003;139:705–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Thomas DR, Hagan JJ. 5-HT7 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3:81–90.

    CAS  PubMed  Google Scholar 

  167. Hedlund PB, Danielson PE, Thomas EA, Slanina K, Carson MJ, Sutcliffe JG. No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc Natl Acad Sci U S A. 2003;100:1375–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Benedict CR, Mathew B, Rex KA, Cartwright Jr J, Sordahl LA. Correlation of plasma serotonin changes with platelet aggregation in an in vivo dog model of spontaneous occlusive coronary thrombus formation. Circ Res. 1986;58:58–67.

    CAS  PubMed  Google Scholar 

  169. Timmons S, Huzoor A, Grabarek J, Kloczewiak M, Hawiger J. Mechanism of human platelet activation by endotoxic glycolipid-bearing mutant Re595 of Salmonella minnesota. Blood. 1986;68:1015–23.

    CAS  PubMed  Google Scholar 

  170. Finocchiaro LM, Arzt ES, Fernandez-Castelo S, Criscuolo M, Finkielman S, Nahmod VE. Serotonin and melatonin synthesis in peripheral blood mononuclear cells: stimulation by interferon-gamma as part of an immunomodulatory pathway. J Interferon Res. 1988;8:705–16.

    CAS  PubMed  Google Scholar 

  171. Kushnir-Sukhov NM, Gilfillan AM, Coleman JW, Brown JM, Bruening S, Toth M, Metcalfe DD. 5-hydroxytryptamine induces mast cell adhesion and migration. J Immunol. 2006;177:6422–32.

    CAS  PubMed  Google Scholar 

  172. Kang BN, Ha SG, Bahaie NS, Hosseinkhani MR, Ge XN, Blumenthal MN, Rao SP, Sriramarao P. Regulation of serotonin-induced trafficking and migration of eosinophils. PLoS One. 2013;8:e54840.

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Boehme SA, Lio FM, Sikora L, Pandit TS, Lavrador K, Rao SP, Sriramarao P. Cutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin. J Immunol. 2004;173:3599–603.

    CAS  PubMed  Google Scholar 

  174. Evans DL, Lynch KG, Benton T, Dube B, Gettes DR, Tustin NB, et al. Selective serotonin reuptake inhibitor and substance P antagonist enhancement of natural killer cell innate immunity in human immunodeficiency virus/acquired immunodeficiency syndrome. Biol Psychiatry. 2008;63:899–905.

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Hernandez ME, Martinez-Fong D, Perez-Tapia M, Estrada-Garcia I, Estrada-Parra S, Pavon L. Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. Eur Neuropsychopharmacol. 2010;20:88–95.

    CAS  PubMed  Google Scholar 

  176. Young MR, Matthews JP. Serotonin regulation of T-cell subpopulations and of macrophage accessory function. Immunology. 1995;84:148–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Muller T, Durk T, Blumenthal B, Grimm M, Cicko S, Panther E, et al. 5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo. PLoS One. 2009;4:e6453.

    PubMed Central  PubMed  Google Scholar 

  178. Sternberg EM, Trial J, Parker CW. Effect of serotonin on murine macrophages: suppression of Ia expression by serotonin and its reversal by 5-HT2 serotonergic receptor antagonists. J Immunol. 1986;137:276–82.

    CAS  PubMed  Google Scholar 

  179. Sternberg EM, Wedner HJ, Leung MK, Parker CW. Effect of serotonin (5-HT) and other monoamines on murine macrophages: modulation of interferon-gamma induced phagocytosis. J Immunol. 1987;138:4360–5.

    CAS  PubMed  Google Scholar 

  180. Nakamura K, Sato T, Ohashi A, Tsurui H, Hasegawa H. Role of a serotonin precursor in development of gut microvilli. Am J Pathol. 2008;172:333–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, et al. Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts. Cancer Res. 2008;68:5152–8.

    CAS  PubMed  Google Scholar 

  182. Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci. 2013;4:48–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Hellstrand K, Czerkinsky C, Ricksten A, Jansson B, Asea A, Kylefjord H, et al. Role of serotonin in the regulation of interferon-gamma production by human natural killer cells. J Interferon Res. 1993;13:33–8.

    CAS  PubMed  Google Scholar 

  184. Kubera M, Kenis G, Bosmans E, Scharpe S, Maes M. Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10. Neuropsychopharmacology. 2000;23:89–98.

    CAS  PubMed  Google Scholar 

  185. Cloez-Tayarani I, Petit-Bertron AF, Venters HD, Cavaillon JM. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. Int Immunol. 2003;15:233–40.

    CAS  PubMed  Google Scholar 

  186. Kubera M, Maes M, Kenis G, Kim YK, Lason W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6. Psychiatry Res. 2005;134:251–8.

    CAS  PubMed  Google Scholar 

  187. Durk T, Panther E, Muller T, Sorichter S, Ferrari D, Pizzirani C, et al. 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol. 2005;17:599–606.

    PubMed  Google Scholar 

  188. Idzko M, Panther E, Stratz C, Muller T, Bayer H, Zissel G, et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004;172:6011–9.

    CAS  PubMed  Google Scholar 

  189. Katoh N, Soga F, Nara T, Tamagawa-Mineoka R, Nin M, Kotani H, Masuda K, Kishimoto S. Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin Exp Immunol. 2006;146:354–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Li N, Ghia JE, Wang H, McClemens J, Cote F, Suehiro Y, et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol. 2011;178:662–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Freire-Garabal M, Nunez MJ, Balboa J, Lopez-Delgado P, Gallego R, Garcia-Caballero T, et al. Serotonin upregulates the activity of phagocytosis through 5-HT1A receptors. Br J Pharmacol. 2003;139:457–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Vollmar P, Nessler S, Kalluri SR, Hartung HP, Hemmer B. The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines. Int J Neuropsychopharmacol. 2009;12:525–36.

    CAS  PubMed  Google Scholar 

  193. Mikulski Z, Zaslona Z, Cakarova L, Hartmann P, Wilhelm J, Tecott LH, et al. Serotonin activates murine alveolar macrophages through 5-HT2C receptors. Am J Physiol Lung Cell Mol Physiol. 2010;299:L272–80.

    CAS  PubMed  Google Scholar 

  194. Seidel MF, Fiebich BL, Ulrich-Merzenich G, Candelario-Jalil E, Koch FW, Vetter H. Serotonin mediates PGE2 overexpression through 5-HT2A and 5-HT3 receptor subtypes in serum-free tissue culture of macrophage-like synovial cells. Rheumatol Int. 2008;28:1017–22.

    CAS  PubMed  Google Scholar 

  195. Menard G, Turmel V, Bissonnette EY. Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2. Clin Exp Immunol. 2007;150:340–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. de las Casas-Engel M, Dominguez-Soto A, Sierra-Filardi E, Bragado R, Nieto C, Puig-Kroger A, et al. Serotonin skews human macrophage polarization through HTR2B and HTR7. J Immunol. 2013;190:2301–10.

    PubMed  Google Scholar 

  197. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229:176–85.

    CAS  PubMed  Google Scholar 

  198. Amireault P, Sibon D, Cote F. Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci. 2013;4:64–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Tian Y, Graf R, El-Badry AM, Lesurtel M, Furrer K, Moritz W, et al. Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice. Hepatology. 2013;53:253–62.

    Google Scholar 

  200. Furrer K, Rickenbacher A, Tian Y, Jochum W, Bittermann AG, Kach A, et al. Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway. Proc Natl Acad Sci U S A. 2011;108:2945–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science. 2006;312:104–7.

    CAS  PubMed  Google Scholar 

  202. Soll C, Jang JH, Riener MO, Moritz W, Wild PJ, Graf R, et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology. 2010;51:1244–54.

    CAS  PubMed  Google Scholar 

  203. Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, Levy RJ. Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161:2111–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Jaffre F, Bonnin P, Callebert J, Debbabi H, Setola V, Doly S, et al. Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy. Circ Res. 2009;104:113–23.

    CAS  PubMed  Google Scholar 

  205. Buskohl PR, Sun ML, Thompson RP, Butcher JT. Serotonin potentiates transforming growth factor-beta3 induced biomechanical remodeling in avian embryonic atrioventricular valves. PLoS One. 2012;7:e42527.

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Rogers TL, Holen I. Tumour macrophages as potential targets of bisphosphonates. J Transl Med. 2011;9:177.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006;66:5527–36.

    CAS  PubMed  Google Scholar 

  208. D’Angelo F, Bernasconi E, Schafer M, Moyat M, Michetti P, Maillard MH, et al. Macrophages promote epithelial repair through hepatocyte growth factor secretion. Clin Exp Immunol. 2013;174:60–72.

    PubMed  Google Scholar 

  209. Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997;94:1441–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Pai VP, Marshall AM, Hernandez LL, Buckley AR, Horseman ND. Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. Breast Cancer Res. 2009;11:R81.

    PubMed Central  PubMed  Google Scholar 

  211. Soll C, Riener MO, Oberkofler CE, Hellerbrand C, Wild PJ, DeOliveira ML, et al. Expression of serotonin receptors in human hepatocellular cancer. Clin Cancer Res. 2012;18:5902–10.

    CAS  PubMed  Google Scholar 

  212. Lesurtel M, Soll C, Humar B, Clavien PA. Serotonin: a double-edged sword for the liver? Surgeon. 2012;10:107–13.

    CAS  PubMed  Google Scholar 

  213. Mann DA, Oakley F. Serotonin paracrine signaling in tissue fibrosis. Biochim Biophys Acta. 1832;2013:905–10.

    Google Scholar 

  214. Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature. 2012;484:105–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010;141:775–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Blank T, Prinz M. Microglia as modulators of cognition and neuropsychiatric disorders. Glia. 2013;61:62–70.

    PubMed  Google Scholar 

  217. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Diaz SL, Doly S, Narboux-Neme N, Fernandez S, Mazot P, Banas SM, et al. 5-HT(2B) receptors are required for serotonin-selective antidepressant actions. Mol Psychiatry. 2012;17:154–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  219. Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, et al. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature. 2010;468:1061–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol. 2004;500:399–411.

    CAS  PubMed  Google Scholar 

  221. Hedlund PB, Sutcliffe JG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci. 2004;25:481–6.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Ministerio de Ciencia e Innovación (SAF2011-23801), Instituto de Salud Carlos III (Red de Investigación en Enfermedades Reumáticas RIER RD12/009, Spanish Network for the Research in Infectious Diseases REIPI RD06/0008, and Red de Investigación en SIDA RIS RD06/0006/1016), and Programa de Actividades de I + D de la Comunidad de Madrid (RAPHYME-CM, S2010/BMD-2350), to ALC.

Author information

Authors and Affiliations

  1. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu, 9, Madrid, 28040, Spain

    Mateo de las Casas-Engel & Angel L. Corbí

Authors
  1. Mateo de las Casas-Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angel L. Corbí
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angel L. Corbí .

Editor information

Editors and Affiliations

  1. Hospital Universitari de Sant Joan, IISPV, URV, Unitat de Recerca Biomèdica, Reus, Spain

    Jordi Camps

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

de las Casas-Engel, M., Corbí, A.L. (2014). Serotonin Modulation of Macrophage Polarization: Inflammation and Beyond. In: Camps, J. (eds) Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics. Advances in Experimental Medicine and Biology, vol 824. Springer, Cham. https://doi.org/10.1007/978-3-319-07320-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation