Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases

  • Ulf Meyer-Hoffert


The skin protects us from water loss and mechanical damage. The surface-exposed epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes, is most important in the barrier defense against these challenges. Endogenous and exogenous proteases such as kallikreins, matriptase, caspases, cathepsins, and proteases derived from microorganisms are important in the desquamation process of the stratum corneum and are able to activate and inactivate defense molecules in human epidermis. Protease inhibitors such as like LEKTI, elafin, SLPI, SERPINs, and cystatins regulate their proteolytic activity and contribute to the integrity and protective barrier function of the skin. Changes in the proteolytic balance of the skin can result in inflammation, which leads to the typical clinical signs of redness, scaling, and itching. This review summarizes the current knowledge of how proteases, their inhibitors, and their target proteins, including filaggrin, protease-activated receptors, and corneodesmosin, contribute to the pathophysiology of inflammation of the skin and highlight their role in common inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis.


atopic dermatitis proteases epidermal barrier innate immunity protease inhibitors psoriasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alef T, Torres S, Hausser I et al (2009) Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J Invest Dermatol 129: 862–869PubMedCrossRefGoogle Scholar
  2. Basel-Vanagaite L, Attia R, Ishida-Yamamoto A et al (2007) Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase. Am J Hum Genet 80: 467–477PubMedCrossRefGoogle Scholar
  3. Bjorck L (1990) Proteinase inhibition, immunoglobulin-binding proteins and a novel antimicrobial principle. Mol Microbiol 4: 1439–1442PubMedCrossRefGoogle Scholar
  4. Bobek LA, Levine MJ (1992) Cystatins – inhibitors of cysteine proteinases. Crit Rev Oral Biol Med 3: 307–332PubMedGoogle Scholar
  5. Brattsand M, Stefansson K, Hubiche T et al (2009) SPINK9: a selective, skin-specific kazal-type serine protease inhibitor. J Invest Dermatol 129: 1656–1665PubMedCrossRefGoogle Scholar
  6. Bugge TH, List K, Szabo R (2007) Matriptase-dependent cell surface proteolysis in epithelial development and pathogenesis. Front Biosci 12: 5060–5070PubMedCrossRefGoogle Scholar
  7. Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6: 328–340PubMedCrossRefGoogle Scholar
  8. Chavanas S, Bodemer C, Rochat A et al (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25: 141–142PubMedCrossRefGoogle Scholar
  9. Cheng T, Hitomi K, Vlijmen-Willems IM et al (2006) Cystatin M/E is a high affinity inhibitor of cathepsin V and cathepsin L by a reactive site that is distinct from the legumain-binding site. A novel clue for the role of cystatin M/E in epidermal cornification. J Biol Chem 281: 15893–15899PubMedCrossRefGoogle Scholar
  10. Dahlen JR, Foster DC, Kisiel W (1997a) Expression, purification, and inhibitory properties of human proteinase inhibitor 8. Biochemistry 36: 14874–14882CrossRefGoogle Scholar
  11. Dahlen JR, Foster DC, Kisiel W (1997b) Human proteinase inhibitor 9 (PI9) is a potent inhibitor of subtilisin A. Biochem Biophys Res Commun 238: 329–333PubMedCrossRefGoogle Scholar
  12. Deleuran M, Ellingsen AR, Paludan K et al (1998) Purified Der p1 and p2 patch tests in patients with atopic dermatitis: evidence for both allergenicity and proteolytic irritancy. Acta Derm Venereol 78: 241–243PubMedCrossRefGoogle Scholar
  13. Demerjian M, Hachem JP, Tschachler E et al (2008) Acute modulations in permeability barrier function regulate epidermal cornification: role of caspase-14 and the protease-activated receptor type 2. Am J Pathol 172: 86–97PubMedCrossRefGoogle Scholar
  14. Denecker G, Hoste E, Gilbert B et al (2007) Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9: 666–674PubMedCrossRefGoogle Scholar
  15. Denecker G, Ovaere P, Vandenabeele P et al (2008) Caspase-14 reveals its secrets. J Cell Biol 180: 451–458PubMedCrossRefGoogle Scholar
  16. Deraison C, Bonnart C, Lopez F et al (2007) LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 18: 3607–3619PubMedCrossRefGoogle Scholar
  17. Descargues P, Deraison C, Bonnart C et al (2005) Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 37: 56–65PubMedGoogle Scholar
  18. Descargues P, Deraison C, Prost C et al (2006) Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin-and chymotrypsin-like hyperactivity in Netherton syndrome. J Invest Dermatol 126: 1622–1632PubMedCrossRefGoogle Scholar
  19. Egberts F, Heinrich M, Jensen JM et al (2004) Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. J Cell Sci 117: 2295–2307PubMedCrossRefGoogle Scholar
  20. Egelrud T (2000) Desquamation in the stratum corneum. Acta Derm Venereol Suppl 208: 44–45Google Scholar
  21. Egelrud T, Brattsand M, Kreutzmann P et al (2005) hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 153: 1200–1203PubMedCrossRefGoogle Scholar
  22. Faurschou M, Borregaard N (2003) Neutrophil granules and secretory vesicles in inflammation. Microbes Infect 5: 1317–1327PubMedCrossRefGoogle Scholar
  23. Frick IM, Akesson P, Herwald H et al (2006) The contact system – a novel branch of innate immunity generating antibacterial peptides. EMBO J 25: 5569–5578PubMedCrossRefGoogle Scholar
  24. Griffiths WA, Leigh IM, Judge MR et al (1998) Disorders of keratinization. In: Champion RH, Breathnach SM, Burns DA(eds) Textbook of Dermatology. Blackwell Science, Oxford, pp 1486–1588Google Scholar
  25. Hachem JP, Houben E, Crumrine D et al (2006a) Serine pro-tease signaling of epidermal ermeability barrier homeostasis. J Invest Dermatol 126: 2074–2086PubMedCrossRefGoogle Scholar
  26. Hachem JP, Wagberg F, Schmuth M et al (2006) Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dermatol 126: 1609–1621PubMedCrossRefGoogle Scholar
  27. Hansson L, Backman A, Ny A et al (2002) Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis. J Invest Dermatol 118: 444–449PubMedCrossRefGoogle Scholar
  28. Hart TC, Hart PS, Bowden DW et al (1999) Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome. J Med Genet 36: 881–887PubMedGoogle Scholar
  29. Hart TC, Hart PS, Michalec MD et al (2000) Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet 37: 88–94PubMedCrossRefGoogle Scholar
  30. Horikoshi T, Igarashi S, Uchiwa H et al (1999) Role of endogenous cathepsin D-like and chymotrypsin-like proteolysis in human epidermal desquamation. Br J Dermatol 141: 453–459PubMedCrossRefGoogle Scholar
  31. Ishida-Yamamoto A, Deraison C, Bonnart C et al (2005) LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. J Invest Dermatol 124: 360–366PubMedCrossRefGoogle Scholar
  32. Ishida-Yamamoto A, Simon M, Kishibe M et al (2004) Epidermal lamellar granules transport different cargoes as distinct aggregates. J Invest Dermatol 122: 1137–1144PubMedCrossRefGoogle Scholar
  33. Jeong SK, Kim HJ, Youm JK et al (2008) Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol 128: 1930–1939PubMedCrossRefGoogle Scholar
  34. Kaiserman D, Whisstock JC, Bird PI (2006) Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med 8: 1–19PubMedCrossRefGoogle Scholar
  35. Kalinin A, Marekov LN, Steinert PM (2001) Assembly of the epidermal cornified cell envelope. J Cell Sci 114: 3069–3070PubMedGoogle Scholar
  36. Kato A, Fukai K, Oiso N et al (2003) Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 148: 665–669PubMedCrossRefGoogle Scholar
  37. Komatsu N, Saijoh K, Toyama T et al (2005) Multiple tissue kallikrein mRNA and protein expression in normal skin and skin diseases. Br J Dermatol 153: 274–281PubMedCrossRefGoogle Scholar
  38. Komatsu N, Suga Y, Saijoh K et al (2006) Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes. J Invest Dermatol 126: 2338–2342PubMedCrossRefGoogle Scholar
  39. Komatsu N, Takata M, Otsuki N et al (2003) Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. J Invest Dermatol 121: 542–549PubMedCrossRefGoogle Scholar
  40. Komiyama T, Gron H, Pemberton PA et al (1996) Interaction of subtilisins with serpins. Protein Sci 5: 874–882PubMedCrossRefGoogle Scholar
  41. Lai-Cheong JE, Arita K, McGrath JA (2007) Genetic diseases of junctions. J Invest Dermatol 127: 2713–2725PubMedCrossRefGoogle Scholar
  42. List K, Currie B, Scharschmidt TC et al (2007) Autosomal ichthyosis with hypotrichosis syndrome displays low matriptase proteolytic activity and is phenocopied in ST14 hypomorphic mice. J Biol Chem 282: 36714–36723PubMedCrossRefGoogle Scholar
  43. Lundwall A, Brattsand M (2008) Kallikrein-related peptidases. Cell Mol Life Sci 65: 2019–2038PubMedCrossRefGoogle Scholar
  44. Magert HJ, Standker L, Kreutzmann P et al (1999) LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem 274: 21499–21502PubMedCrossRefGoogle Scholar
  45. Meyer-Hoffert U, Wichmann N, Schwichtenberg L et al (2003) Supernatants of Pseudomonas aeruginosa induce the Pseudomonas-specific antibiotic elafin in human keratinocytes. Exp Dermatol 12: 418–425PubMedCrossRefGoogle Scholar
  46. Meyer-Hoffert U, Wingertszahn J, Wiedow O (2004) Human leukocyte elastase induces keratinocyte proliferation by epidermal growth factor receptor activation. J Invest Dermatol 123: 338–345PubMedCrossRefGoogle Scholar
  47. Meyer-Hoffert U, Wu Z, Schröder JM (2009) Identification of lympho-epithelial Kazal-type inhibitor 2 in human skin as a kallikrein-related peptidase 5-specific protease inhibitor. PLoS ONE 4: e4372PubMedCrossRefGoogle Scholar
  48. Mitsudo K, Jayakumar A, Henderson Y et al (2003) Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 42: 3874–3881PubMedCrossRefGoogle Scholar
  49. Morar N, Willis-Owen SA, Moffatt MF (2006) The genetics of atopic dermatitis. J Allergy Clin Immunol 118: 24–34PubMedCrossRefGoogle Scholar
  50. Munch J, Standker L, Adermann K et al (2007) Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129: 263–275PubMedCrossRefGoogle Scholar
  51. Nelson D, Potempa J, Kordula T et al (1999) Purification and characterization of a novel cysteine proteinase (periodontain) from Porphyromonas gingivalis. Evidence for a role in the inactivation of human alpha1-proteinase inhibitor. J Biol Chem 274: 12245–12251PubMedCrossRefGoogle Scholar
  52. Netzel-Arnett S, Currie BM, Szabo R et al (2006) Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 281: 32941–32945PubMedCrossRefGoogle Scholar
  53. Nishio Y, Noguchi E, Shibasaki M et al (2003) Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immun 4: 515–517PubMedCrossRefGoogle Scholar
  54. Nordahl EA, Rydengard V, Nyberg P et al (2004) Activation of the complement system generates antibacterial peptides. Proc Natl Acad Sci USA 101: 16879–16884PubMedCrossRefGoogle Scholar
  55. Ossovskaya VS, Bunnett NW (2004) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84: 579–621PubMedCrossRefGoogle Scholar
  56. Palmer CN, Irvine AD, Terron-Kwiatkowski A et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38: 441–446PubMedCrossRefGoogle Scholar
  57. Pham CT, Ivanovich JL, Raptis SZ et al (2004) Papillon-Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J Immunol 173: 7277–7281PubMedGoogle Scholar
  58. Pham CT, Ley TJ (1999) Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci USA 96: 8627–8632PubMedCrossRefGoogle Scholar
  59. Rao NV, Rao GV, Hoidal JR (1997) Human dipeptidyl-peptidase I. Gene characterization, localization, and expression. J Biol Chem 272: 10260–10265PubMedCrossRefGoogle Scholar
  60. Rawlings AV, Harding CR (2004) Moisturization and skin barrier function. Dermatol Ther 17(suppl 1): 43–48PubMedCrossRefGoogle Scholar
  61. Resing KA, Thulin C, Whiting K et al (1995) Characterization of profilaggrin endoproteinase 1. A regulated cytoplasmic endoproteinase of epidermis. J Biol Chem 270: 28193–28198PubMedCrossRefGoogle Scholar
  62. Resing KA, Walsh KA, Dale BA (1984) Identification of two intermediates during processing of profilaggrin to filaggrin in neonatal mouse epidermis. J Cell Biol 99: 1372–1378PubMedCrossRefGoogle Scholar
  63. Resing KA, Walsh KA, Haugen-Scofield J et al (1989) Identi-fication of proteolytic cleavage sites in the conversion of profilaggrin to filaggrin in mammalian epidermis. J Biol Chem 264: 1837–1845PubMedGoogle Scholar
  64. Rogalski C, Meyer-Hoffert U, Proksch E et al (2002) Human leukocyte elastase induces keratinocyte proliferation in vitro and in vivo. J Invest Dermatol 118: 49–54PubMedCrossRefGoogle Scholar
  65. Sandilands A, O’Regan GM, Liao H et al (2006) Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol 126: 1770–1775PubMedCrossRefGoogle Scholar
  66. Schechter NM, Choi EJ, Wang ZM et al (2005) Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Biol Chem 386: 1173–1184PubMedCrossRefGoogle Scholar
  67. Silverman GA, Bartuski AJ, Cataltepe S et al (1998) SCCA1 and SCCA2 are proteinase inhibitors that map to the serpin cluster at 18q21.3. Tumour Biol 19: 480–487PubMedCrossRefGoogle Scholar
  68. Smith FJ, Irvine AD, Terron-Kwiatkowski A et al (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38: 337–342PubMedCrossRefGoogle Scholar
  69. Sondell B, Thornell LE, Egelrud T (1995) Evidence that stratum corneum chymotryptic enzyme is transported to the stratum corneum extracellular space via lamellar bodies. J Invest Dermatol 104: 819–823PubMedCrossRefGoogle Scholar
  70. Stefansson K, Brattsand M, Roosterman D et al (2008) Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol 128: 18–25PubMedCrossRefGoogle Scholar
  71. Steinhoff M, Buddenkotte J, Shpacovitch V et al (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 26: 1–43PubMedCrossRefGoogle Scholar
  72. Stewart GA, Thompson PJ (1996) The biochemistry of common aeroallergens. Clin Exp Allergy 26: 1020–1044PubMedCrossRefGoogle Scholar
  73. Toomes C, James J, Wood AJ et al (1999) Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23: 421–424PubMedCrossRefGoogle Scholar
  74. Turk V, Bode W (1991) The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 285: 213–219PubMedCrossRefGoogle Scholar
  75. Walley AJ, Chavanas S, Moffatt MF et al (2001) Gene polymorphism in Netherton and common atopic disease. Nat Genet 29: 175–178PubMedCrossRefGoogle Scholar
  76. Walz M, Kellermann S, Bylaite M et al (2007) Expression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesis. Exp Dermatol 16: 715–723PubMedCrossRefGoogle Scholar
  77. Weidinger S, Baurecht H, Wagenpfeil S et al (2008) Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 122: 560–568PubMedCrossRefGoogle Scholar
  78. Wiedow O, Harder J, Bartels J et al (1998) Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem Biophys Res Commun 248: 904–909PubMedCrossRefGoogle Scholar
  79. Wiedow O, Luademann J, Utecht B (1991) Elafin is a potent inhibitor of proteinase 3. Biochem Biophys Res Commun 174: 6–10PubMedCrossRefGoogle Scholar
  80. Wiedow O, Meyer-Hoffert U (2005) Neutrophil serine pro-teases: potential key regulators of cell signalling during inflammation. J Intern Med 257: 319–328PubMedGoogle Scholar
  81. Wiedow O, Muhle K, Streit V et al (1996) Human eosinophils lack human leukocyte elastase. Biochim Biophys Acta 1315: 185–187PubMedGoogle Scholar
  82. Wiedow O, Schröder JM, Gregory H et al (1990) Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem 265: 14791–14795PubMedGoogle Scholar
  83. Wiedow O, Wiese F, Christophers E (1995) Lesional elastase activity in psoriasis. Diagnostic and prognostic significance. Arch Dermatol Res 287: 632–635PubMedCrossRefGoogle Scholar
  84. Wiedow O, Young JA, Davison MD et al (1993) Antileukoprotease in psoriatic scales. J Invest Dermatol 101: 305–309PubMedCrossRefGoogle Scholar
  85. Winton HL, Wan H, Cannell MB et al (1998) Class specific inhibition of house dust mite proteinases which cleave cell adhesion, induce cell death and which increase the permeability of lung epithelium. Br J Pharmacol 124: 1048–1059PubMedCrossRefGoogle Scholar
  86. Wu Z, Hansmann B, Meyer-Hoffert U et al (2009) Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family. Identification and characterization of filaggrin-2 – a novel member of the S100 fused-type protein family – in human skin. PLoS ONE 4: e5227PubMedCrossRefGoogle Scholar
  87. Wu Z, Meyer-Hoffert U, Reithmayer K et al (2009) Highly complex peptide aggregates of the S100 fused-type protein hornerin are present in human skin. J Invest Dermatol 129: 1446–1458PubMedCrossRefGoogle Scholar
  88. Yamasaki K, Di Nardo A, Bardan A et al (2007) Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 13: 975–980PubMedCrossRefGoogle Scholar
  89. Yamasaki K, Schauber J, Coda A et al (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J 20: 2068–2080PubMedCrossRefGoogle Scholar
  90. Yasueda H, Mita H, Akiyama K et al (1993) Allergens from Dermatophagoides mites with chymotryptic activity. Clin Exp Allergy 23: 384–390PubMedCrossRefGoogle Scholar
  91. Yousef GM, Diamandis EP (2001) The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 22: 184–204PubMedCrossRefGoogle Scholar
  92. Zeeuwen PL, Vlijmen-Willems IM, Hendriks W et al (2002) A null mutation in the cystatin M/E gene of ichq mice causes juvenile lethality and defects in epidermal cornification. Hum Mol Genet 11: 2867–2875PubMedCrossRefGoogle Scholar
  93. Zeeuwen PL, Vlijmen-Willems IM, Olthuis D et al (2004) Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice. Hum Mol Genet 13: 1069–1079PubMedCrossRefGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009

Authors and Affiliations

  1. 1.Department of DermatologyUniversity Hospital Schleswig-HolsteinKielGermany

Personalised recommendations