Neurotrophins and neuropeptides as inflammatory mediators in case of chronic dermatosis

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This literature review examines the role of neurotrophins and neuropeptides for the development of skin inflammatory reactions in case of chronic inflammatory dermatoses. The article describes inflammatory effects of neurotrophin, a nerve growth factor, neuropeptide substance P and calcitonin gene-related peptide. Factors affecting the condition of skin innervation and development of inflammation - neurotrophin, a nerve growth factor, amphiregulin, an epidermal growth factor, and semaphorin 3A, a nerve repulsion factor - were examined. Searching for and administering antagonists of proinflammatory effects of neuropeptides, neurotrophins and epidermal growth factor can become new approaches to the treatment of chronic inflammatory dermatoses.

About the authors

A. A. Kubanova

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Author for correspondence.
Russian Federation

V. A. Smolyannikova

I.M. Sechenov First Moscow State Medical University

Russian Federation

V. V. Chikin

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Russian Federation

A. E. Karamova

State Research Center of Dermatovenereology and Cosmetology, Ministry of Healthcare of the Russian Federation

Russian Federation


  1. Peters E.M., Ericson M.E., Hosoi J. et al. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol 2006; 126: 1937-1947.
  2. Shepherd A.J., Downing J.E., Miyan J.A. Without nerves, immunology remains incomplete - in vivo veritas. Immunology 2005; 116: 145-163.
  3. Raap U., Kapp A. Neuroimmunological findings in allergic skin diseases. Curr Opin Allergy Clin Immunol 2005; 5: 419-424.
  4. Tausk F., Elenkov I., Moynihan J. Psychoneuroimmunology. Dermatol Ther 2008; 21: 22-31.
  5. Peters E.M., Liezmann C., Klapp B.F., Cruse J. The neuroimmune connection interferes with tissue regeneration and chronic inflammatory disease in the skin. Ann NY Acad Sci 2012; 1262 (1): 118-126.
  6. Ашмарин И.П., Каразеева Е.П. Нейропептиды в кн. «Нейрохимия» / Под ред. И.П. Ашмарина, П.В. Стукалова. М: Изд-во Института биомедицинской химии РАМН, 1996; глава 9: 296-333.
  7. Громов Л.А. Нейропептиды. Киев: Здоровье 1992; 245.
  8. Church M.K., el-Lati S., Caulfield J.P. Neuropeptide-induced secretion from human skin mast cells. Int Arch Allergy Appl Immunol 1991; 94: 310-318.
  9. Kawana S., Liang Z., Nagano M., Suzuki H. Role of substance P in stress-derived degranulation of dermal mast cells in mice. J Dermatol Sci 2006; 42 (1): 47-54.
  10. Ansel J.C., Brown J.R., Payan D.G., Brown M.A. Substance P selectively activates TNF-alpha gene expression in murine mast cells. J Immunol 1993; 150: 4478-4485.
  11. Steinhoff M., Stander S., Seeliger S. et al. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 2003; 139: 1479-1488.
  12. Hakim-Rad K., Metz M., Maurer M. Mast cells: makers and breakers of allergic inflammation. Curr Opin Allergy Clin Immunol 2009; 9: 427-430.
  13. Kawakami T., Ando T., Kimura M. et al. Mast cells in atopic dermatitis. Curr Opin Immunol 2009; 21: 666-678.
  14. Lindsey K.Q., Caughman S.W., Olerud J.E. et al. Neural regulation of endothelial cell-mediated inflammation. J Investig Dermatol Symp Proc 2000; 5: 74-78.
  15. Quinlan K.L., Song I.S., Naik S.M. et al. VCAM-1 expression on human dermal microvascular endothelial cells is directly and specifically up-regulated by substance P. J Immunol 1999; 162: 1656-1661.
  16. Foster A.P., Cunningham F.M. Substance P induces activation, adherence and migration of equine eosinophils. J Vet Pharmacol Ther 2003; 26: 131-138.
  17. Feistritzer C., Clausen J., Sturn D.H. et al. Natural killer cell functions mediated by the neuropeptide substance P. Regul Pept 2003; 116: 119-126.
  18. Von Restoroff B., Kemeny L., Michel G. et al. Specific binding of substance P in normal human keratinocytes. J Invest Dermatol 1992; 98: 510.
  19. Payan D.G., Brewster D.R., Goetzl E.J. Stereospecific receptors for substance P on cultured human IM-9 limphoblasts. J Immunol 1984; 133: 3260-3264.
  20. Levite M. Neuropeptides, by direct interaction with T-cells, induce cytokine secretion and break the commitment to a distinct T helper phenotype. Proc Natl Acad Sci USA 1998; 95: 12544-12549.
  21. Kang H., Byun D.G., Kim J.W. Effects of substance P and vasoactive intestinal peptide on interferongamma and interleukin-4 production in severe atopic dermatitis. Ann Allergy Asthma Immunol 2000; 85: 227-232.
  22. Lambrecht B.N. Immunologists getting nervous: neuropeptides, dendritic cells and T-cell activation. Respir Res 2001; 2: 133-138.
  23. Scholzen T.E., Steinhoff M., Sindrilaru A. et al. Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage. FASEB J 2004; 18: 1007-1009.
  24. Kim K.H., Park K.C., Chung J.H. et al. The effect of substance P on peripheral blood mononuclear cells in patients with atopic dermatitis. J Dermatol Sci 2003; 32: 115-124.
  25. Stanisz A.M., Befus D., Bienenstock J. Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer’s patches, mesenteric lymph nodes, and spleen. J Immunol 1986; 136: 152-156.
  26. Lai J.-P., Douglas S.D., Ho W.-Z. Human lymphocytes express substance P and its receptor. J Neuroimmunol 1998; 86: 80-86.
  27. Lotti T., Bianchi B., Panconesi E. Neuropeptides and skin disorders. The new frontiers of neuro-endocrinecutaneous immunology. Int J Dermatol 1999; 38: 673-675.
  28. Mantyh P.W. Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 2002; 63 (Suppl. 11): P. 6-10.
  29. Marriott I., Bost K.L. Expression of authentic substance P receptors in murine and human dendritic cells. J Neuroimmunol 2001; 114: 131-141.
  30. Casale T.B. Neuropeptides and the lung. J Allergy Clin Immunol 1991; 88 (1): 1-14.
  31. Garibyan L., Rheingold C.G., Lerner E.A. Understanding the pathophysiology of itch. Dermatol Ther 2013; 26 (2): 84-91.
  32. Stead R.H., Tomioka M., Quinonez G. et al. Intestinal mucosal mast cells in normal and nematode infected rat intestines are in intimate contact with peptidergic nerves. Proc Natl Acad Sci USA 1987; 84: 2975-2979.
  33. Naukkarinen A., Järvikallio A., Lakkakorpi J. et al. Quantitative histochemical analysis of mast cells and sensory nerves in psoriatic skin. J Pathol 1996; 180: 200-205.
  34. Steinhoff M., Vergnolle N., Young S.H. et al. Agonist of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 2000; 6: 151-158.
  35. Xing L., Guo J., Wang X. Induction and expression of p-calcitonin gene-related peptide in rat T-lymphocytes and its significance. J Immunol 2000; 165: 4359-4366.
  36. Bracci-Laudiero L., Aloe L., Caroleo M.C. et al. Endogenous NGF regulates CGRP expression in human monocytes and affects HLA-DR and CD86 expression and IL-10 production. Blood 2005; 106: 3507-3514.
  37. Brain S.D., Grant A.D. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004; 84: 903-934.
  38. Takahashi K., Nakanishi S., Imamura S. Direct effects of cutaneous neuropeptides on adenylylcyclase activity and proliferation in a keratinocyte cell line: stimulation of cyclic AMP formation by CGRP and VIP/PHM, and inhibition by NPY through G protein-coupled receptors. J Invest Dermatol 1993; 101: 646-651.
  39. Wallengren J. Vasoactive peptides in the skin. J Investig Dermatol Symp Proc 1997; 2: 49-55.
  40. Ansel J.C., Armstrong C.A., Song I. et al. Interactions of the skin and nervous system. J Investig Dermatol Symp Proc 1997; 2: 23-26.
  41. Datta S.K., Sabet M., Nguyen K.P. et al. Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax. Proc Natl Acad Sci USA 2010; 107 (23): 10638-10643.
  42. Mikami N., Matsushita H., Kato T. et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T-cell functions. J Immunol 2011; 186 (12): 6886-6893.
  43. Antûnez C., Torres M.J., Lôpez S. et al. Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigenpositive T-cells in patients with atopic dermatitis. Br J Dermatol 2009; 161 (3): 547-553.
  44. Hosoi J., Murphy G.F., Egan C.L. et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993; 363: 159-163.
  45. Sun Y.G., Zhao Z.Q., Meng X.L. et al. Cellular basis of itch sensation. Science 2009; 325 (5947): 1531-1534.
  46. Patel K.N., Dong X. Itch: cells, molecules, and circuits. ACS Chem Neurosci 2011; 2: 17-25.
  47. Tominaga M., Takamori K. Recent advances in the study of itching. an update on peripheral mechanisms and treatments of itch. Biol Pharm Bull 2013; 36 (8) 1241-1247.
  48. Chang S.E., Han S.S., Jung H.J., Choi J.H. Neuropeptides and their receptors in psoriatic skin in relation to pruritus. Br J Dermatol 2007; 156: 1272-1277.
  49. Tominaga M., Ogawa H., Takamori K. Decreased production of semaphorin 3A in the lesional skin of atopic dermatitis. Br J Dermatol 2008; 158: 842-844.
  50. Ikoma A., Rukwied R., Stander S. et al. Neurophysiology of pruritus: interaction of pain and itch. Arch Dermatol 2003; 139 (11): 1475-1478.
  51. Nilsson A., Kanje M. Amphiregulin acts as an autocrine survival factor for adult sensory neurons. Neuroreport 2005 28; 16 (3): 213-218.
  52. Tominaga M., Ozawa S., Tengara S. et al. Intraepidermal nerve fibers increase in dry skin of acetone-treated mice. J Dermatol Sci 2007; 48 (2): 103-111.
  53. Yuen E.C., Howe C.L., Li Y. et al. Nerve growth factor and the neurotrophic factor hypothesis. Brain Dev 1996; 18 (5): 362-368.
  54. Botchkarev V.A., Eichmuller S., Peters E.M. et al. A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle-dependent changes in mast cell-nerve fiber contacts in murine skin. Arch Dermatol Res 1997; 289: 292-302.
  55. Tron V.A., Coughlin M.D., Jang D.E. et al. Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest. 1990; 85: 1085-1089.
  56. Pincelli C., Sevignani C., Manfredini R. et al. Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes. J Invest Dermatol 1994; 103: 12-18.
  57. Marconi A., Terracina M., Fila C. et al. Expression and function of neurotrophins and their receptors in cultured human keratinocytes. J Invest Dermatol. 2003; 121: 1515-1521.
  58. Botchkarev V.A., Yaar M., Peters E.M. et al. Neurotrophins in skin biology and pathology. J Invest Dermatol. 2006; 126: 1718-1727.
  59. Tanaka A., Matsuda H. Expression of nerve growth factor in itchy skin of atopic NC/NgaTnd Mice. J Vet Med Sci 2005; 67 (9): 915-919.
  60. Di Marco E., Marchisio P.C., Bondanza M. et al. Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem 1991; 266: 21718-21722.
  61. Di Marco E., Mathor M., Bondanza S. et al. Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulates their growth by a novel autocrine loop. J Biol Chem 1993; 268: 22838-22846.
  62. Marconi A., Vaschieri C., Zanoli S. et al. Nerve growth factor protects human keratinocytes from ultraviolet-B-induced apoptosis. J Invest Dermatol. 1999; 113: 920-927.
  63. Kanda N., Watanabe S. Histamine enhances the production of nerve growth factor in human keratinocytes. J Invest Dermatol. 2003; 121: 570-577.
  64. Takaoka K., Shirai Y., Saito N. Inflammatory cytokine tumor necrosis-а enhances nerve growth factor production in human keratinocytes, HaCaT-cells. Pharmacol Sci 2009; 111: 381-391.
  65. Bruni A., Bigon E., Boarato E. et al. Interaction between nerve growth factor and lysophosphatidylserine on rat peritoneal mast cells. FEBS Lett 1982; 138: 190-192.
  66. Roosterman D., Goerge T., Schneider D.W. et al. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev 2006; 86: 1309-1379.
  67. Berasain C., Avila M.A. Amphiregulin. Semin Cell Dev Biol 2014; 28: 31-41.
  68. Cook P.W., Piepkorn M., Clegg C.H. et al. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Invest 1997; 100: 2286-2294.
  69. Cook P.W., Brown J.R., Cornell K.A., Pittelkow M.R. Suprabasal expression of human amphiregulin in the epidermis of transgenic mice induces a severe, early-onset, psoriasis-like skin pathology: expression of amphiregulin in the basal epidermis is also associated with synovitis. Exp Dermatol 2004; 13: 347-356.
  70. Pastore S., Mascia F., Mariani V., Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008; 128: 1365-1374.
  71. Fukamachi S., Bito T., Shiraishi N. et al. Modulation of semaphorin 3A expression by calcium concentration and histamine in human keratinocytes and fibroblasts. J Dermatol Sci 2011; 61 (2): 118-123.
  72. Tominaga M., Ozawa S., Ogawa H., Takamori K. A hypothetical mechanism of intraepidermal neurite formation in NC/Nga mice with atopic dermatitis. J Dermatol Sci. 2007; 46 (3): 199-210.
  73. Tominaga M., Kamo A., Tengara S. et al. In vitro model for penetration of sensory nerve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritus. Br J Dermatol. 2009; 161 (5): 1028-1037.
  74. Fujisawa H. Discovery of semaphoring receptors, neutropilin and plexin, and their functions in neural development. J Neurobiol 2004; 59: 24-33.
  75. Neufeld G., Kessler O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 2008; 8: 632-645.
  76. Lepelletier Y., Moura I.C., Hadj-Slimane R. et al. Immunosuppressive role of semaphorin-3A on T-cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 2006; 36:1782-1793.
  77. Catalano A., Caprari P., Moretti et al. Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 2006; 107 (8): 3321-3329.
  78. Suzuki K., Kumanogoh A., Kikutani H. Semaphorins and their receptors in immune cell interactions. Nat Immunol 2008; 9 (1): 17-23.

Copyright (c) 2014 Kubanova A.A., Smolyannikova V.A., Chikin V.V., Karamova A.E.

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