Advertisement

Neurotoxicity Research

, Volume 28, Issue 2, pp 147–153 | Cite as

Mast Cell Serotonin Immunoregulatory Effects Impacting on Neuronal Function: Implications for Neurodegenerative and Psychiatric Disorders

  • P. Conti
  • Y. B. Shaik-Dasthagirisaheb
Review

Abstract

Mast cells (MCs) are derived from hemopoietic precursor cells, undergo their maturation in peripheral tissues, and play a significant role in both the innate and adaptive immune response. Cross-linking of the FcεRI on MCs initiates activation of several cytoplasmic protein tyrosine kinases which rapidly lead to phosphorylation and recruitment of adaptor molecules. These effects trigger the release of preformed mediators stored in the cytoplasmic granules, including histamine, serotonin and tryptase, as well as newly synthesized mediators, such as cytokines/chemokines, prostaglandins, leukotrienes, and growth factors. Serotonin (5-HT) is a bioactive monoamine, which has seven specific cell surface membrane bound receptors which are coupled to G-proteins, plays an important role in the central and peripheral nervous system, and is one of the key mediators in signaling between nervous and immune systems. Serotonin is not stored in all MC types but is implicated in MC adhesion, chemotaxis, tumorigenesis, and tissue regeneration through smooth muscle differentiation of stromal cells. Recent evidence indicates that serotonin has immunoregulatory actions that may be important in neuropsychiatric conditions. Chemokines, RANTES/CCL5, MCP-1/CCL2, and related molecules, constitute the C–C class of chemokine supergene family, play a role in regulating T helper-cell cytokine production and MC trafficking, and are involved in histamine and serotonin generation and MC functions. Pro-inflammatory cytokines such as interleukin-1-β and tumor necrosis factor which mediate MC response, are capable of activating p38 MAPK, and might increase serotonin generation through p38 MAPK activation. Here, we review the relationship between MCs and serotonin and its role in inflammatory diseases and neuroimmune interactions.

Keywords

Serotonin Mast cells Inflammation Immunity Mediators 

References

  1. Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20(2):131–147PubMedCrossRefGoogle Scholar
  2. Ahern GP (2011) 5-HT and the immune system. Curr Opin Pharmacol 11(1):29–33PubMedCentralPubMedCrossRefGoogle Scholar
  3. Ando T, Matsumoto K, Namiranian S, Yamashita H, Glatthorn H, Kimura M, Dolan BR, Lee JJ, Galli SJ, Kawakami Y, Jamora C, Kawakami T (2013) Mast cells are required for full expression of allergen/SEB-induced skin inflammation. J Invest Dermatol 133(12):2695–2705PubMedCrossRefGoogle Scholar
  4. Aune TM, McGrath KM, Sarr T, Bombara MP, Kelley KA (1993) Expression of 5-HT1A receptors on activated human T cells. Regulation of cyclic AMP levels and T cell proliferation by 5-hydroxytryptamine. J Immunol 151(3):1175–1183PubMedGoogle Scholar
  5. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (1999) Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev 13(10):1297–1308PubMedCentralPubMedCrossRefGoogle Scholar
  6. Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ (2011) Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 131(9):1853–1860PubMedCrossRefGoogle Scholar
  7. Boyd ND, Leeman SE (1987) Multiple actions of substance P that regulate the functional properties of acetylcholine receptors of clonal rat PC12 cells. J Physiol 389:69–97PubMedCentralPubMedCrossRefGoogle Scholar
  8. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL, Theoharides TC (2005) Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 174(12):7665–7675PubMedCrossRefGoogle Scholar
  9. Castellani ML, Kempuraj D, Salini V, Vecchiet J, Tete S, Ciampoli C, Conti F, Cerulli G, Caraffa A, Antinolfi P, Theoharides TC, De Amicis D, Perrella A, Cuccurullo C, Boscolo P, Shaik Y (2009) The latest interleukin: IL-33 the novel IL-1-family member is a potent mast cell activator. J Biol Regul Homeost Agents 23(1):11–14PubMedGoogle Scholar
  10. Conti P, Boucher W, Letourneau R, Feliciani C, Reale M, Barbacane RC, Vlagopoulos P, Bruneau G, Thibault J, Theoharides TC (1995) Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5-HT release. Immunology 86(3):434–440PubMedCentralPubMedGoogle Scholar
  11. Dinarello CA (2005) An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity 23(5):461–462PubMedCrossRefGoogle Scholar
  12. Enerbäck L (1965) Mast cells in carcinoid tumours. Distribution, histochemical properties and 5-hydroxytryptamine content. Acta Pathol Microbiol Scand 64(4):491–505PubMedGoogle Scholar
  13. Frydas S, Varvara G, Murmura G, Saggini A, Caraffa A, Antinolfi P, Tete’ S, Tripodi D, Conti F, Cianchetti E, Toniato E, Rosati M, Speranza L, Pantalone A, Saggini R, Di Tommaso LM, Theoharides TC, Conti P, Pandolfi F (2013) Impact of capsaicin on mast cell inflammation. Int J Immunopathol Pharmacol 26(3):597–600PubMedGoogle Scholar
  14. Gemma C, Smith EM, Hughes TK Jr, Opp MR (2000) Human immunodeficiency virus glycoprotein 160 induces cytokine mRNA expression in the rat central nervous system. Cell Mol Neurobiol 20(4):419–431PubMedCrossRefGoogle Scholar
  15. Gordon JR, Galli SJ (1991) Release of both preformed and newly synthesized tumor necrosis factor alpha (TNF-alpha)/cachectin by mouse mast cells stimulated via the Fc epsilon RI. A mechanism for the sustained action of mast cell-derived TNF-alpha during IgE-dependent biological responses. J Exp Med 174(1):103–107PubMedCrossRefGoogle Scholar
  16. Gruba SM, Meyer AF, Manning BM (2014) Time- and concentration-dependent effects of exogenous serotonin and inflammatory cytokines on mast cell function. ACS Chem Biol 9(2):503–509PubMedCentralPubMedCrossRefGoogle Scholar
  17. Hajj Hussein I, Eid A, Maksoud R, Jambart S, Bou Assi T, Zgheib Z, Oueidat D, Chams N, Chams S, Diab R, Barada K, Jurjus R, Cappello F, Reimund J, Kreiker J, Leone A, Jurjus A (2014) Estrogens control inflammation in experimental colitis. J Biol Regul Homeost Agents 28(2):213–224PubMedGoogle Scholar
  18. Hirota N, McCuaig S, O’Sullivan MJ, Martin JG (2014) Serotonin augments smooth muscle differentiation of bone marrow stromal cells. Stem Cell Res 12(3):599–609PubMedCrossRefGoogle Scholar
  19. Hu R, Tang F (2009) Effect of Weichang Anwan on NO and 5-HT in blood serum, SP and MC in colon in IBS-D rats. Zhongguo Zhong Yao Za Zhi 34(23):3073–3077PubMedGoogle Scholar
  20. Jara LJ, Vera-Lastra O, Miranda JM, Alcala M, Alvarez-Nemegyei J (2001) Prolactin in human systemic lupus erythematosus. Lupus 10(10):748–756PubMedCrossRefGoogle Scholar
  21. Jha SK, Ross RJ, Morrison AR (2005) Sleep-related neurons in the central nucleus of the amygdala of rats and their modulation by the dorsal raphe nucleus. Physiol Behav 86(4):415–426PubMedCrossRefGoogle Scholar
  22. Juremalm M, Olsson N, Nilsson G (2005) CCL17 and CCL22 attenuate CCL5-induced mast cell migration. Clin Exp Allergy 35(6):708–712PubMedCrossRefGoogle Scholar
  23. Karamitopoulou E, Shoni M, Theoharides TC (2014) Increased number of non-degranulated mast cells in pancreatic ductal adenocarcinoma but not in acute pancreatitis. Int J Immunopathol Pharmacol 27(2):213–220PubMedGoogle Scholar
  24. Kielian T, Bearden ED, Baldwin AC, Esen N (2004) IL-1 and TNF-alpha play a pivotal role in the host immune response in a mouse model of Staphylococcus aureus-induced experimental brain abscess. J Neuropathol Exp Neurol 63(4):381–396PubMedGoogle Scholar
  25. Kim K (2012) Neuroimmunological mechanism of pruritus in atopic dermatitis focused on the role of serotonin. Biomol Ther (Seoul) 2(6):506–512CrossRefGoogle Scholar
  26. Klimek V, Zak-Knapik J, Mackowiak M (1994) Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. J Psychiatry Neurosci 19(1):63–67PubMedCentralPubMedGoogle Scholar
  27. Komiyama Y, Andoh A, Fujiwara D, Ohmae H, Araki Y, Fujiyama Y, Mitsuyama K, Kanauchi O (2011) New prebiotics from rice bran ameliorate inflammation in murine colitis models through the modulation of intestinal homeostasis and the mucosal immune system. Scand J Gastroenterol 46(1):40–52PubMedCrossRefGoogle Scholar
  28. Kritas SK, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P, Toniato E, Pantalone A, Neri G, Frydas S, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Cerulli G, Theoharides TC, Conti P (2013a) Impact of mast cells on the skin. Int J Immunopathol Pharmacol 26(4):855–859PubMedGoogle Scholar
  29. Kritas SK, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P, Toniato E, Pantalone A, Neri G, Frydas S, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Theoharides TC, Conti P (2013b) Mast cell involvement in rheumatoid arthritis. J Biol Regul Homeost Agents 27(3):655–660PubMedGoogle Scholar
  30. Kritas SK, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P, Toniato E, Pantalone A, Neri G, Frydas S, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Cerulli G, Theoharides TC, Conti P (2013c) Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 27(4):955–959PubMedGoogle Scholar
  31. Kritas SK, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P, Toniato E, Pantalone A, Neri G, Frydas S, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Cerulli G, Theoharides TC, Conti P (2013d) Impact of mast cells in rejection of allografts. Eur J Inflamm 11(3):609–614Google Scholar
  32. Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A, Rosati M, Tei M, Speziali A, Saggini R, Conti P (2014a) Relationship between serotonin and mast cells: inhibitory effect of anti-serotonin. J Biol Regul Homeost Agents 28(3):377–380PubMedGoogle Scholar
  33. Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A, Saggini R, Frydas S, Rosati M, Tei M, Speziali A, Pandolfi F, Conti P (2014b) Interrelationship between IL-3 and mast cells. J Biol Regul Homeost Agents 28(1):17–21PubMedGoogle Scholar
  34. Kritas SK, Saggini A, Cerulli G, Speziali A, Caraffa A, Antinolfi P, Pantalone A, Rosati M, Tei M, Saggini R, Conti P (2014c) Asthma and mast cell biology. Eur J Inflamm 12(2):261–265Google Scholar
  35. Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A, Rosati M, Tei M, Speziali A, Saggini R, Conti P (2014d) Corticotropin-releasing hormone, microglia and mental disorders. Int J Immunopathol Pharmacol 27(2):163–167PubMedGoogle Scholar
  36. Kushnir-Sukhov NM, Brown JM, Wu Y, Kirshenbaum A, Metcalfe DD (2007) Human mast cells are capable of serotonin synthesis and release. J Allergy Clin Immunol 119:498–499PubMedCrossRefGoogle Scholar
  37. Kushnir-Sukhov NM, Brittain E, Scott L, Metcalfe DD (2008) Clinical correlates of blood serotonin levels in patients with mastocytosis. Eur J Clin Invest 38(12):953–958PubMedCentralPubMedCrossRefGoogle Scholar
  38. Maleki-Dizaji N, Eteraf-Oskouei T, Fakhrjou A, Maljaie SH, Garjani A (2010) The effects of 5-HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation. Int Immunopharmacol 10(9):1010–1016PubMedCrossRefGoogle Scholar
  39. Mashayekhi Goyonlo V, Elnour H, Nordlind K (2014) Serotonin transporter protein overexpression and association to Th17 and T regulatory cells in lupoid leishmaniasis. Arch Dermatol Res 306(2):181–188PubMedCrossRefGoogle Scholar
  40. Metcalfe DD (1984) Mast cell mediators with emphasis on intestinal mast cells. Ann Allergy 53(6 Pt 2):563–575PubMedGoogle Scholar
  41. Meuer S, Ecker U, Hadding U, Bitter-Suermann D (1981) Platelet-serotonin release by C3a and C5a: two independent pathways of activation. J Immunol 126(4):1506–1509PubMedGoogle Scholar
  42. Nordlind K, Azmitia EC, Slominski A (2008) The skin as a mirror of the soul: exploring the possible roles of serotonin. Exp Dermatol 17(4):301–311PubMedCrossRefGoogle Scholar
  43. Noro M, Antonijevic I, Forray C, Kasper S, Kocabas NA, Lecrubier Y, Linotte S, Mendlewicz J, Montgomery S, Snyder L, Souery D, Verbanck P, Zohar J, Massat I (2010) 5-HT1A and 5-HT2A receptor genes in treatment response phenotypes in major depressive disorder. Int Clin Psychopharmacol 25(4):228–231PubMedCrossRefGoogle Scholar
  44. Panula P, Kaartinen M, Mäcklin M, Costa E (1985) Histamine-containing peripheral neuronal and endocrine systems. J Histochem Cytochem 33(9):933–941PubMedCrossRefGoogle Scholar
  45. Papaliodis D, Boucher W, Kempuraj D, Michaelian M, Wolfberg A, House M, Theoharides TC (2008) Niacin-induced “flush” involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model. J Pharmacol Exp Ther 327(3):665–672PubMedCrossRefGoogle Scholar
  46. Papathanasiou E, Palaska I, Theoharides TC (2013) Stress hormones regulate periodontal inflammation. J Biol Regul Homeost Agents 27(3):621–626PubMedGoogle Scholar
  47. Petra AI, Panagiotidou S, Stewart JM, Conti P, Theoharides TC (2014) Spectrum of mast cell activation disorders. Expert Rev Clin Immunol 10(6):729–739PubMedCrossRefGoogle Scholar
  48. Prevete N, Staiano RI, Granata F, Detoraki A, Necchi V, Ricci V, Triggiani M, De Paulis A, Marone G, Genovese A (2013) Expression and function of Angiopoietins and their tie receptors in human basophils and mast cells. J Biol Regul Homeost Agents 27(3):827–839PubMedGoogle Scholar
  49. Ritter M, El-Nour H, Hedblad MA, Butterfield JH, Beck O, Stephanson N, Holst M, Giscombe R, Azmitia EC, Nordlind K (2012) Serotonin and its 5-HT1 receptor in human mastocytosis. Immunopharmacol Immunotoxicol 34(4):679–685PubMedCrossRefGoogle Scholar
  50. Sepiashvili RI, Balmasova IP, Staurina LN (2013) Serotonin and its immune and physiological effects. Ross Fiziol Zh Im I M Sechenova 99(1):17–32PubMedGoogle Scholar
  51. Shaik-Dasthagirisaheb YB, Varvara G, Murmura G, Saggini A, Caraffa A, Antinolfi P, Tetè S, Rosati M, Cianchetti E, Toniato E, Speranza L, Pantalone A, Saggini R, Di Tommaso LM, Conti P, Theoharides TC, Pandolfi F (2013a) Inhibitor effect of antioxidant flavonoids quercitin, and capsaicin in mast cell inflammation. Eur J Inflamm 11(2):353–357Google Scholar
  52. Shaik-Dasthagirisaheb YB, Varvara G, Murmura G, Saggini A, Potalivo G, Caraffa A, Antinolfi P, Tete’ S, Tripodi D, Conti F, Cianchetti E, Toniato E, Rosati M, Conti P, Speranza L, Pantalone A, Saggini R, Theoharides TC, Pandolfi F (2013b) Vascular endothelial growth factor (VEGF), mast cells and inflammation. Int J Immunopathol Pharmacol. 26(2):327–335 (Review) PubMedGoogle Scholar
  53. Sharkey KA, Mawe GM (2002) Neuroimmune and epithelial interactions in intestinal inflammation. Curr Opin Pharmacol 2(6):669–677PubMedCrossRefGoogle Scholar
  54. Sodhi MS, Burnet PW, Makoff AJ, Kerwin RW, Harrison PJ (2001) RNA editing of the 5-HT2C receptor is reduced in schizophrenia. Mol Psychiatry 6(4):373–379PubMedCrossRefGoogle Scholar
  55. Sommer C (2004) Serotonin in pain and analgesia: actions in the periphery. Mol Neurobiol 30(2):117–125PubMedCrossRefGoogle Scholar
  56. Spangelo BL, Farrimond DD, Pompilius M, Bowman KL (2000) Interleukin-1 beta and thymic peptide regulation of pituitary and glial cell cytokine expression and cellular proliferation. Ann NY Acad Sci 917:597–607PubMedCrossRefGoogle Scholar
  57. Starkl P, Marichal T, Galli SJ (2013) PLA2G3 promotes mast cell maturation and function. Nat Immunol 14(6):527–529PubMedCentralPubMedCrossRefGoogle Scholar
  58. Stefulj J, Cicin-Sain L, Schauenstein K, Jernej B (2001) Serotonin and immune response: effect of the amine on in vitro proliferation of rat lymphocytes. NeuroImmunoModulation 9(2):103–108PubMedCrossRefGoogle Scholar
  59. Suter MR, Wen YR, Decosterd I, Ji RR (2007) Do glial cells control pain? Neuron Glia Biol 3(3):255–268PubMedCentralPubMedCrossRefGoogle Scholar
  60. Theoharides TC, Kempuraj D, Iliopoulou BP (2007) Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 601:423–430 (Review) PubMedCrossRefGoogle Scholar
  61. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, Alysandratos KD, Kalogeromitros D, Asadi S, Stavrianeas N, Peterson E, Leeman S, Conti P (2010) IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA 107(9):4448–4453PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Immunology Division, Post-graduate Medical SchoolUniversity of Chieti-PescaraChietiItaly
  2. 2.Section of Infectious Diseases, Department of MedicineBoston University Medical CenterBostonUSA

Personalised recommendations