Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection

Abstract

Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. coli–killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli–killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn2+-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn2+ sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Identification of psoriasin as an E. coli–killing protein.
Figure 2: Psoriasin shows antimicrobial activity preferentially against E. coli in various salt and pH conditions.
Figure 3: Psoriasin is focally expressed in human skin and some adnexal structures.
Figure 4: E. coli is effectively killed on human skin and the E. coli–killing activity is inhibited in vivo by a neutralizing antibody to psoriasin.
Figure 5: Psoriasin is secreted in vivo on the body surface.
Figure 6: Bacteria and proinflammatory cytokines induce psoriasin.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Klenha, J. & Krs, V. Lysozyme in mouse and human skin. J. Invest. Dermatol. 49, 396–399 (1967).

  2. 2

    Wiedow, O., Harder, J., Bartels, J., Streit, V. & Christophers, E. Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem. Biophys. Res. Commun. 248, 904–909 (1998).

  3. 3

    Harder, J. & Schroder, J.M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem. 277, 46779–46784 (2002).

  4. 4

    Schittek, B. et al. Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat. Immunol. 2, 1133–1137 (2001).

  5. 5

    Harder, J., Bartels, J., Christophers, E. & Schroder, J.M. A peptide antibiotic from human skin. Nature 387, 861 (1997).

  6. 6

    Harder, J., Bartels, J., Christophers, E. & Schroder, J.M. Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276, 5707–5713 (2001).

  7. 7

    Frohm, M. et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272, 15258–15263 (1997).

  8. 8

    Nizet, V. et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454–457 (2001).

  9. 9

    Ong, P.Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002).

  10. 10

    Casewell, M.W. & Desai, N. Survival of multiply-resistant Klebsiella aerogenes and other gram-negative bacilli on finger-tips. J. Hosp. Infect. 4, 350–360 (1983).

  11. 11

    Noble, W.C. in The skin microflora and microbial disease (ed. Noble, W.C.) 210 (Cambridge University Press, Cambridge, UK, 1992).

  12. 12

    Kulski, J.K., Lim, C.P., Dunn, D.S. & Bellgard, M. Genomic and phylogenetic analysis of the S100A7 (Psoriasin) gene duplications within the region of the S100 gene cluster on human chromosome 1q21. J. Mol. Evol. 56, 397–406 (2003).

  13. 13

    Steinberg, D.A. & Lehrer, R.I. Designer assays for antimicrobial peptides. Disputing the “one-size-fits-all” theory. Methods Mol. Biol. 78, 169–186 (1997).

  14. 14

    van der Merwe, D.E. et al. Biological variation in sweat sodium chloride conductivity. Ann. Clin. Biochem. 39, 39–43 (2002).

  15. 15

    Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

  16. 16

    Lagasse, E. & Clerc, R.G. Cloning and expression of two human genes encoding calcium-binding proteins that are regulated during myeloid differentiation. Mol. Cell. Biol. 8, 2402–2410 (1988).

  17. 17

    Murthy, A.R., Lehrer, R.I., Harwig, S.S. & Miyasaki, K.T. In vitro candidastatic properties of the human neutrophil calprotectin complex. J. Immunol. 151, 6291–6301 (1993).

  18. 18

    Clohessy, P.A. & Golden, B.E. Calprotectin-mediated zinc chelation as a biostatic mechanism in host defence. Scand. J. Immunol. 42, 551–556 (1995).

  19. 19

    Sohnle, P.G., Hunter, M.J., Hahn, B. & Chazin, W.J. Zinc-reversible antimicrobial activity of recombinant calprotectin (migration inhibitory factor-related proteins 8 and 14). J. Infect. Dis. 182, 1272–1275 (2000).

  20. 20

    Shumaker, D.K., Vann, L.R., Goldberg, M.W., Allen, T.D. & Wilson, K.L. TPEN, a Zn2+/Fe2+ chelator with low affinity for Ca2+, inhibits lamin assembly, destabilizes nuclear architecture and may independently protect nuclei from apoptosis in vitro. Cell Calcium 23, 151–164 (1998).

  21. 21

    Madsen, P. et al. Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. J. Invest. Dermatol. 97, 701–712 (1991).

  22. 22

    Burgisser, D.M. et al. Amino acid sequence analysis of human S100A7 (psoriasin) by tandem mass spectrometry. Biochem. Biophys. Res. Commun. 217, 257–263 (1995).

  23. 23

    Hagens, G. et al. Calcium-binding protein S100A7 and epidermal-type fatty acid-binding protein are associated in the cytosol of human keratinocytes. Biochem. J. 339, 419–427 (1999).

  24. 24

    Celis, J.E. et al. Bladder squamous cell carcinomas express psoriasin and externalize it to the urine. J. Urol. 155, 2105–2112 (1996).

  25. 25

    Leygue, E. et al. Differential expression of psoriasin messenger RNA between in situ and invasive human breast carcinoma. Cancer Res. 56, 4606–4609 (1996).

  26. 26

    Yoshio, H. et al. Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense. Pediatr. Res. 53, 211–216 (2003).

  27. 27

    Heizmann, C.W., Fritz, G. & Schafer, B.W. S100 proteins: structure, functions and pathology. Front. Biosci. 7, d1356–1368 (2002).

  28. 28

    Eckert, R.L. et al. S100 proteins in the epidermis. J. Invest. Dermatol. 123, 23–33 (2004).

  29. 29

    Cole, A.M. et al. Calcitermin, a novel antimicrobial peptide isolated from human airway secretions. FEBS Lett. 504, 5–10 (2001).

  30. 30

    Travis, S.M. et al. Bactericidal activity of mammalian cathelicidin-derived peptides. Infect. Immun. 68, 2748–2755 (2000).

  31. 31

    Brodersen, D.E., Nyborg, J. & Kjeldgaard, M. Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free states. Biochemistry 38, 1695–1704 (1999).

  32. 32

    Ashoori, M. et al. Antibacterial activities of new synthetic divalent cation chelators. Microbiol. Immunol. 43, 311–316 (1999).

  33. 33

    Gort, A.S., Ferber, D.M. & Imlay, J.A. The regulation and role of the periplasmic copper, zinc superoxide dismutase of Escherichia coli. Mol. Microbiol. 32, 179–191 (1999).

  34. 34

    Benov, L., Sage, H. & Fridovich, I. The copper- and zinc-containing superoxide dismutase from Escherichia coli: molecular weight and stability. Arch. Biochem. Biophys. 340, 305–310 (1997).

  35. 35

    Imlay, J.A. Pathways of oxidative damage. Annu. Rev. Microbiol. 57, 395–418 (2003).

  36. 36

    Steinman, H.M. Function of periplasmic copper-zinc superoxide dismutase in Caulobacter crescentus. J. Bacteriol. 175, 1198–1202 (1993).

  37. 37

    Sampson, B. et al. Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism. Lancet 360, 1742–1745 (2002).

  38. 38

    Schroder, J.M. Identification and structural characterization of chemokines in lesional skin material of patients with inflammatory skin disease. Methods Enzymol. 288, 266–297 (1997).

  39. 39

    Lange, H., Solterbeck, M., Berek, C. & Lemke, H. Correlation between immune maturation and idiotypic network recognition. Eur. J. Immunol. 26, 2234–2242 (1996).

  40. 40

    Lange, H. et al. Reversal of the adult IgE high responder phenotype in mice by maternally transferred allergen-specific monoclonal IgG antibodies during a sensitive period in early ontogeny. Eur. J. Immunol. 32, 3133–3141 (2002).

Download references

Acknowledgements

The authors thank H. Janssen, J. Quitzau, M. Brandt, K. Schultz, C. Butzek-Mehrens, A. Preschke, I. Erichsen, R. Rohde, S. Voss and K. Klose (Departments of Dermatology, Medical Microbiology and Otorhinolaryngology, University of Kiel) for technical assistance; D. Blankenburg and H. Pönicke (Department of Dermatology, University of Kiel) for photography; M. Weichenthal (Department of Dermatology, University of Kiel) for statistics; and L. Schwichtenberg, P. Velasco, S. Schubert and H. Lemke (Departments of Dermatology, Medical Microbiology and Biochemistry, University of Kiel) for discussions. Supported by the Deutsche Forschungsgemeinschaft (SFB 617) and in part by the Hensel-Stiftung Kiel.

Author information

Correspondence to Jens-Michael Schröder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Exposure to human skin kills E. coli. (PDF 105 kb)

Supplementary Fig. 2

Purification and isolation of psoriasin. (PDF 285 kb)

Supplementary Fig. 3

Psoriasin bactericidal activity does not cause morphological changes and is not inhibited by Fe2+ and Ca2+. (PDF 284 kb)

Supplementary Fig. 4

The E. coli-killing activity of human skin is inhibited by preincubation with Zn2+ or a neutralizing psoriasin antibody. (PDF 186 kb)

Supplementary Fig. 5

Skin secretes bioactive psoriasin in vivo. (PDF 84 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gläser, R., Harder, J., Lange, H. et al. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 6, 57–64 (2005). https://doi.org/10.1038/ni1142

Download citation

Further reading