Cell Biology and Toxicology

, Volume 33, Issue 4, pp 389–405 | Cite as

Upregulated expression of substance P (SP) and NK1R in eczema and SP-induced mast cell accumulation

  • Mengmeng Zhan
  • Wenjiao Zheng
  • Qijun Jiang
  • Zuotao Zhao
  • Zhiyun Wang
  • Junling Wang
  • Huiyun Zhang
  • Shaoheng HeEmail author
Original Article


Substance P (SP) was reported to be associated with eczema and acts as a potent skin mast cell secretagogue. However, little is known of its expression in inflammatory cells in eczema and its ability in induction of mast cell accumulation. In the present study, we investigated expression of SP and neurokinin-1 receptor (NK1R) on peripheral blood leukocytes and mast cells from patients with eczema and influence of SP on mast cell accumulation by using flow cytometry analysis, trans-epithelial cell migration assay and mouse peritoneal model. The results showed that plasma SP and IL-17A levels in eczema patients were higher than that in healthy control subject. The percentages of SP+ and NK1R+ expression populations of monocytes, helper T cells, natural killer T cells and basophils in peripheral blood of eczema patients were markedly elevated. It was observed that not only absolute number of mast cells but also SP+ and NK1R+ mast cells are enhanced in the lesion skin of eczema. SP showed a potent chemoattractant action on mast cells as assessed by a mouse peritoneal model and a trans-endothelium cell migration assay. SP-induced mast cell accumulation appears a CD18/CD11a complex, l-selectin and ICAM-1-dependent event which can be blocked by a NK-1R antagonist RP67580. In conclusion, elevated expression of SP in patients with eczema and the ability of SP in induction of mast cell accumulation indicate strongly that SP is a potent proinflammatory mediator, which contributes to the pathogenesis of eczema. Inhibitors of SP and blockers of NK1R are likely useful agents for treatment of eczema.


Mast cell Substance P NK1R IL-17 Eczema 



Intercellular Adhesion Molecule 1




Mean fluorescence intensity


Neurokinin-1 receptor


Substance P



This project was sponsored by the grants from the “12th Five-Year ” National Science and Technology Support Plan (2014BAI07B02), the National Natural Science Foundation of China (No. 81172836, 81471592, 81472016), Project of Scientific Research Special Fund for Public Industry in Forestry (201304103), Major Science and Technology Platform for Institution of Higher Education in Liaoning province (2014168), “Twelfth five-year” public welfare industry special scientific research project (2015SQ00136), Program for Liaoning Innovation Research Team in University (LNIRT, LT2013017), Climbing Scholar Project for Institution of Higher Education in Liaoning province (2013222), Allergic Disease Translational Medicine Research Center of Liaoning Province (2015225016), Liaoning Provincial Engineering Research Center for Diagnosing & Treating Inflammatory Disease (20141093), Clinical Capability Construction Project for Liaoning Provincial Hospitals (LNCCC-A06-2014, LNCCC-D26-2015), the National Natural Science Foundation of Liaoning Province (2014022027, 2014022019, 201601358) and Science and Technology Planning Project of Suzhou (SYS201272).

Authors’ contribution

Mengmeng Zhan and Wenjiao Zheng carried out most experiments, generated the majority of the data and wrote large part of the first draft of the paper. Qijun Jiang and Zuotao Zhao took part in the clinical study and participated in data analysis and study design. Junling Wang and Zhiyun Wang took part in ELISA, flow cytometry, immunochemistry, cell culture and challenge test and wrote a part of the first draft of the paper. Huiyun Zhang and Shaoheng He designed and conducted the study, analyzed the data and wrote the second and final drafts of the paper. All authors read and approved the final paper.

Compliance with ethical standards

The informed consent from each volunteer according to the Declaration of Helsinki and agreement with the ethical committee of the First Affiliated Hospital of Jinzhou Medical University were obtained.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Ando T, Matsumoto K, Namiranian S, Yamashita H, Glatthorn H, Kimura M, et al. Mast cells are required for full expression of allergen/SEB-induced skin inflammation. J Invest Dermatol. 2013;133(12):2695–705.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Azimi E, Reddy VB, Shade KC, Anthony RM, Talbot S, Pereira PJ, et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI insight. 2016;1(16):e89362.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bretterklieber A, Beham-Schmid C, Sturm GJ, Berghold A, Brezinschek R, Aberer W, et al. Anaphylaxis with clonal mast cells in normal looking skin - a new entity? Allergy. 2015;70(7):864–72.CrossRefPubMedGoogle Scholar
  4. Caulfield JP, el-Lati S, Thomas G, Church MK. Dissociated human foreskin mast cells degranulate in response to anti-IgE and substance P. Lab Investig. 1990;63(4):502–10.PubMedGoogle Scholar
  5. Chang C, Keen CL, Gershwin ME. Treatment of eczema. Clin Rev Allergy Immunol. 2007;33(3):204–25.CrossRefPubMedGoogle Scholar
  6. Cima K, Vogelsinger H, Kahler CM. Sensory neuropeptides are potent chemoattractants for human basophils in vitro. Regul Pept. 2010;160(1–3):42–8.CrossRefPubMedGoogle Scholar
  7. Erin N, Ersoy Y, Ercan F, Akici A, Oktay S. NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats. Clin Exp Dermatol. 2004;29(6):644–8.CrossRefPubMedGoogle Scholar
  8. Fatima S, Rafiq A, Majid Z. Harlequin ichthyosis in an infant born to a father with eczema. J Trop Pediatr. 2015;61(2):143–5.CrossRefPubMedGoogle Scholar
  9. Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, et al. Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. The Journal of allergy and clinical immunology. 2014;134(3):622–33. e9CrossRefPubMedGoogle Scholar
  10. Garcia-Recio S, Gascon P. Biological and pharmacological aspects of the NK1-receptor. Biomed Res Int. 2015;2015:495704.CrossRefPubMedPubMedCentralGoogle Scholar
  11. He S, Peng Q, Walls AF. Potent induction of a neutrophil and eosinophil-rich infiltrate in vivo by human mast cell tryptase: selective enhancement of eosinophil recruitment by histamine. J Immunol. 1997;159(12):6216–25.PubMedGoogle Scholar
  12. He S, Gaca MD, Walls AF. A role for tryptase in the activation of human mast cells: modulation of histamine release by tryptase and inhibitors of tryptase. J Pharmacol Exp Ther. 1998;286(1):289–97.PubMedGoogle Scholar
  13. He S, Zhang H, Chen H, Yang H, Huang T, Chen Y, et al. Expression and release of IL-29 by mast cells and modulation of mast cell behavior by IL-29. Allergy. 2010;65(10):1234–41.CrossRefPubMedGoogle Scholar
  14. He S, Zhang H, Zeng X, Yang P. Self-amplification mechanisms of mast cell activation: a new look in allergy. Curr Mol Med. 2012;12(10):1329–39.CrossRefPubMedGoogle Scholar
  15. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther. 2003;305(3):1212–21.CrossRefPubMedGoogle Scholar
  16. Kimata H. Exposure to road traffic enhances allergic skin wheal responses and increases plasma neuropeptides and neurotrophins in patients with atopic eczema/dermatitis syndrome. Int J Hyg Environ Health. 2004;207(1):45–9.CrossRefPubMedGoogle Scholar
  17. Koon HW, Shih D, Karagiannides I, Zhao D, Fazelbhoy Z, Hing T, et al. Substance P modulates colitis-associated fibrosis. Am J Pathol. 2010;177(5):2300–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lange L, Rietschel E, Hunzelmann N, Hartmann K. Elevated levels of tryptase in children with nummular eczema. Allergy. 2008;63(7):947–9.CrossRefPubMedGoogle Scholar
  19. Leonardi S, Cuppari C, Manti S, Filippelli M, Parisi GF, Borgia F, et al. Serum interleukin 17, interleukin 23, and interleukin 10 values in children with atopic eczema/dermatitis syndrome (AEDS): association with clinical severity and phenotype. Allergy Asthma Proc. 2015;36(1):74–81.CrossRefPubMedGoogle Scholar
  20. Liu X, Jin H, Zhang G, Lin X, Chen C, Sun J, et al. Intratumor IL-17-positive mast cells are the major source of the IL-17 that is predictive of survival in gastric cancer patients. PLoS One. 2014;9(9):e106834.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liu X, Wang J, Zhang H, Zhan M, Chen H, Fang Z, et al. Induction of mast cell accumulation by tryptase via a protease activated receptor-2 and ICAM-1 dependent mechanism. Mediat Inflamm. 2016;2016:6431574.Google Scholar
  22. Matsuda H, Kawakita K, Kiso Y, Nakano T, Kitamura Y. Substance P induces granulocyte infiltration through degranulation of mast cells. J Immunol. 1989;142(3):927–31.PubMedGoogle Scholar
  23. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237–41.CrossRefPubMedGoogle Scholar
  24. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201(2):167–80.CrossRefPubMedGoogle Scholar
  25. Pavlovic S, Liezmann C, Blois SM, Joachim R, Kruse J, Romani N, et al. Substance P is a key mediator of stress-induced protection from allergic sensitization via modified antigen presentation. J Immunol. 2011;186(2):848–55.CrossRefPubMedGoogle Scholar
  26. Ribbing C, Engblom C, Lappalainen J, Lindstedt K, Kovanen PT, Karlsson MA, et al. Mast cells generated from patients with atopic eczema have enhanced levels of granule mediators and an impaired Dectin-1 expression. Allergy. 2011;66(1):110–9.CrossRefPubMedGoogle Scholar
  27. Rosso M, Munoz M, Berger M. The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. Sci World J. 2012;2012:381434.Google Scholar
  28. Schultz Larsen F, Hanifin JM. Secular change in the occurrence of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1992;176:7–12.Google Scholar
  29. Sun J, Bhatia M. Substance P at the neuro-immune crosstalk in the modulation of inflammation, asthma and antimicrobial host defense. Inflamm Allergy Drug Targets. 2014;13(2):112–20.CrossRefPubMedGoogle Scholar
  30. Wechsler JB, Hsu CL, Bryce PJ. IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation. The Journal of allergy and clinical immunology. 2014;133(6):1735–43.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Weinstock JV. Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta Physiol (Oxf). 2015;213(2):453–61.CrossRefGoogle Scholar
  32. Yano H, Wershil BK, Arizono N, Galli SJ. Substance P-induced augmentation of cutaneous vascular permeability and granulocyte infiltration in mice is mast cell dependent. J Clin Invest. 1989;84(4):1276–86.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Zamuner SR, Zuliani JP, Fernandes CM, Gutierrez JM, de Fatima Pereira Teixeira C. Inflammation induced by Bothrops asper venom: release of proinflammatory cytokines and eicosanoids, and role of adhesion molecules in leukocyte infiltration. Toxicon. 2005;46(7):806–13.CrossRefPubMedGoogle Scholar
  34. Zheng W, Wang J, Zhu W, Xu C, He S. Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P. Cell Biol Toxicol. 2016;32(3):217–28.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Mengmeng Zhan
    • 1
  • Wenjiao Zheng
    • 1
  • Qijun Jiang
    • 2
  • Zuotao Zhao
    • 3
  • Zhiyun Wang
    • 1
  • Junling Wang
    • 1
  • Huiyun Zhang
    • 1
    • 4
  • Shaoheng He
    • 1
    Email author
  1. 1.Allergy and Clinical Immunology Research Centrethe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouPeople’s Republic of China
  2. 2.Department of DermatologyDonggang Central HospitalDonggangChina
  3. 3.Department of Dermatology and VenerologyPeking University First HospitalBeijingChina
  4. 4.Department of pathophysiologyJinzhou Medical UniversityJinzhouChina

Personalised recommendations