Inflammation Research

, Volume 67, Issue 7, pp 609–616 | Cite as

Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients

  • F. D’Amico
  • M. Granata
  • E. Skarmoutsou
  • C. Trovato
  • G. Lovero
  • P. Gangemi
  • V. Longo
  • M. Pettinato
  • M. C. Mazzarino
Original Research Paper


The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis.


S100A8/A9 Calprotectin Psoriasis Biological therapy 



This work was supported by intramural grants from the University of Catania, Italy.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, Gelfand JM. Psoriasis and comorbid diseases: epidemiology. J Am Acad Dermatol. 2017;76:377–90.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Chandra A, Ray A, Senapati S, Chatterjee R. Genetic and epigenetic basis of psoriasis pathogenesis. Mol Immunol. 2015;64:313–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Pollock RA, Abji F, Gladman DD. Epigenetics of psoriatic disease: a systematic review and critical appraisal. J Autoimmun. 2017;78:29–38.CrossRefPubMedGoogle Scholar
  4. 4.
    Harden JL, Krueger JG, Bowcock AM. The immunogenetics of Psoriasis: a comprehensive review. J Autoimmun. 2015;64:66–73.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013;34:174–81.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, Pestonjamasp V, Piraino J, Huttner K, Gallo RL. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;22:414:454–7.CrossRefGoogle Scholar
  7. 7.
    Niyonsaba F, Kiatsurayanon C, Chieosilapatham P, Ogawa H. Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases. Exp Dermatol. 2017;26:989–98.CrossRefPubMedGoogle Scholar
  8. 8.
    Abtin A, Eckhart L, Gläser R, Gmeiner R, Mildner M, Tschachler E. The antimicrobial heterodimer S100A8/S100A9 (calprotectin) is upregulated by bacterial flagellin in human epidermal keratinocytes. J Invest Dermatol. 2010;130:2423–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004;104:4260–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Ehrchen JM, Sunderkötter C, Foell D, Vogl T, Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol. 2009;86:557–66.CrossRefPubMedGoogle Scholar
  11. 11.
    Kerkhoff C, Voss A, Scholzen TE, Averill MM, Zänker KS, Bornfeldt KE. Novel insights into the role of S100A8/A9 in skin biology. Exp Dermatol. 2012;21:822–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Broome AM, Ryan D, Eckert RL. S100 protein subcellular localization during epidermal differentiation and psoriasis. J Histochem Cytochem. 2003;51:675–85.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Benoit S, Toksoy A, Ahlmann M, Schmidt M, Sunderkötter C, Foell D, Pasparakis M, Roth J. Goebeler M.Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis. Br J Dermatol. 2006;155:62–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Semprini S, Capon F, Tacconelli A, Giardina E, Orecchia A, Mingarelli R, Gobello T, Zambruno G, Botta A, Fabrizi G, Novelli G. Evidence for differential S100 gene over-expression in psoriatic patients from genetically heterogeneous pedigrees. Hum Genet. 2002;111:310–3.CrossRefPubMedGoogle Scholar
  15. 15.
    Langkilde A, Olsen LC, Sætrom P, Drabløs F, Besenbacher S, Raaby L, Johansen C, Iversen L. Pathway analysis of skin from psoriasis patients after adalimumab treatment reveals new early events in the anti-inflammatory mechanism of anti-TNF-α. PLoS One. 2016;11:e0167437.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Benson JM, Sachs CW, Treacy G, Zhou H, Pendley CE, Brodmerkel CM, Shankar G, Mascelli MA. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat Biotechnol. 2011;29:615–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Varghese F, Bukhari AB, Malhotra R, De A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One. 2014;9:e96801.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhang LJ, Gallo RL. Antimicrobial peptides. Curr Biol. 2016;26:R14–R9.CrossRefPubMedGoogle Scholar
  20. 20.
    Pruenster M, Vogl T, Roth J, Sperandio M. S100A8/A9: from basic science to clinical application. Pharmacol Ther. 2016;167:120–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Srikrishna G. S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun. 2012;4:31–40.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu L, Okano S, Takahara M, Chiba T, Tu Y, Oda Y, Furue M. Expression of S100 protein family members in normal skin and sweat gland tumors. J Dermatol Sci. 2013;70:211–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Schonthaler HB, Guinea-Viniegra J, Wculek SK, Ruppen I, Ximenez-Embun P, Guio-Carrion A, Navarro R, Hogg N, Ashman K, Wagner EF. S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3. Immunity. 2013;39:1171–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Hiroshima Y, Sakamoto E, Yoshida K, Abe K, Naruishi K, Yamamoto T, Shinohara Y, Kido JI, Geczy CL. Advanced glycation end-products and Porphyromonas gingivalis lipopolysaccharide increase calprotectin expression in human gingival epithelial cells. J Cell Biochem. 2018;119:1591–603.CrossRefPubMedGoogle Scholar
  25. 25.
    Lee Y, Jang S, Min JK, et al. S100A8 and S100A9 are messengers in the crosstalk between epidermis and dermis modulating a psoriatic milieu in human skin. Biochem Biophys Res Commun. 2012;423:647–53.CrossRefPubMedGoogle Scholar
  26. 26.
    Yen T, Harrison CA, Devery JM, Leong S, Iismaa SE, Yoshimura T, Geczy CL. Induction of the S100 chemotactic protein, CP-10, in murine microvascular endothelial cells by proinflammatory stimuli. Blood. 1997;90:4812–21.PubMedGoogle Scholar
  27. 27.
    Zhong A, Xu W, Zhao J, Xie P, Jia S, Sun J, Galiano RD, Mustoe TA, Hong SJ. S100A8 and S100A9 are induced by decreased hydration in the epidermis and promote fibroblast activation and fibrosis in the dermis. Am J Pathol. 2016;186:109–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Xu K, Geczy CL. IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8. J Immunol. 2000;164:4916–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Chiricozzi A, Guttman-Yassky E, Suárez-Fariñas M, Nograles KE, Tian S, Cardinale I, Chimenti S, Krueger JG. Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol. 2011;131:677–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Witte E, Kokolakis G, Witte K, Philipp S, Doecke WD, Babel N, Wittig BM, Warszawska K, Kurek A, Erdmann-Keding M, Kunz S, Asadullah K, Kadin ME, Volk HD, Sterry W, Wolk K, Sabat R. IL-19 is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis. J Invest Dermatol. 2014;134:2757–67.CrossRefPubMedGoogle Scholar
  31. 31.
    Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272:9496–502.CrossRefPubMedGoogle Scholar
  32. 32.
    Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007;81:28–37.CrossRefPubMedGoogle Scholar
  33. 33.
    Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005;174:3695–702.CrossRefPubMedGoogle Scholar
  34. 34.
    Johansen C, Vinter H, Soegaard-Madsen L, Olsen LR, Steiniche T, Iversen L, Kragballe K. Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy. Br J Dermatol. 2010;163:1194–204.CrossRefPubMedGoogle Scholar
  35. 35.
    Balato A, Schiattarella M, Di Caprio R, Lembo S, Mattii M, Balato N, Ayala F. Effects of adalimumab therapy in adult subjects with moderate-to-severe psoriasis on Th17 pathway. J Eur Acad Dermatol Venereol. 2014;28:1016–24.CrossRefPubMedGoogle Scholar
  36. 36.
    Luan L, Han S, Wang H, Liu X. Down-regulation of the Th1, Th17, and Th22 pathways due to anti-TNF-α treatment in psoriasis. Int Immunopharmacol. 2015;29:278–84.CrossRefPubMedGoogle Scholar
  37. 37.
    Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Fuentes-Duculan J, Novitskaya I, Khatcherian A, Bluth MJ, Lowes MA, Krueger JG. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204:3183–94.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang F, Smith N, Maier L, Xia W, Hammerberg C, Chubb H, Chen C, Riblett M, Johnston A, Gudjonsson JE, Helfrich Y, Kang S, Fisher GJ, Voorhees JJ. Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24. Br J Dermatol. 2012;167:92–102.CrossRefPubMedGoogle Scholar
  39. 39.
    Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology. 2010;49:1215–28.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Silva LC, Ortigosa LC, Benard G. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy. 2010;2:817–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203:2271–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sofen H, Smith S, Matheson RT, Leonardi CL, Calderon C, Brodmerkel C, Li K, Campbell K, Marciniak SJ Jr, Wasfi Y, Wang Y, Szapary P, Krueger JG. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133:1032–40.CrossRefPubMedGoogle Scholar
  43. 43.
    D’Amico F, Trovato C, Skarmoutsou E, Rossi GA, Granata M, Longo V, Gangemi P, Pettinato M, Mazzarino MC. Effects of adalimumab, etanercept and ustekinumab on the expression of psoriasin (S100A7) in psoriatic skin. J Dermatol Sci. 2015;80:38–44.CrossRefPubMedGoogle Scholar
  44. 44.
    Ekman AK, Vegfors J, Eding CB, Enerbäck C. Overexpression of psoriasin (S100A7) contributes to dysregulated differentiation in psoriasis. Acta Derm Venereol. 2017;97:441–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • F. D’Amico
    • 1
  • M. Granata
    • 1
  • E. Skarmoutsou
    • 1
  • C. Trovato
    • 1
  • G. Lovero
    • 1
  • P. Gangemi
    • 2
  • V. Longo
    • 3
  • M. Pettinato
    • 3
  • M. C. Mazzarino
    • 1
  1. 1.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  2. 2.Servizio di Anatomia PatologicaAzienda Ospedaliera Universitaria Policlinico-Vittorio EmanueleCataniaItaly
  3. 3.Unità Operativa Complessa di DermatologiaAzienda Ospedaliera Universitaria Policlinico-Vittorio EmanueleCataniaItaly

Personalised recommendations