Abstract
Protease regulation plays a crucial role in skin homeostasis and inflammation as revealed by the identification of loss-of-function mutations in SPINK5 (serine protease inhibitor of Kazal type 5) in Netherton sydrome (NS). SPINK5 encodes LEKTI (lympho-epithelial Kazal type related inhibitor), a multidomain serine protease inhibitor expressed in all stratified epithelia. Our laboratory has developed a number of murine models which have been instrumental in dissecting the pathogenesis of NS. This minireview discusses the major findings of these models and emphasizes the role of protease regulation, especially kallikrein-related peptidases in NS.
Funding source: Agence Nationale de la Recherche
Award Identifier / Grant number: ANR-08-GENO-033
Funding statement: This work was supported by the French Ministry of Health, the Agence Nationale de la Recherche (ANR-08-GENO-033), French Foundation for Medical Research (FRM-DAL20051205066), the National Agency for Research (Netherlink: ANR-05-MRAR-009 01/NS2AD:ANR-08-GENO-033) and the E-Rare Joint Transnational Call for Projects on Rare Diseases (KLKIN).
Acknowledgments
This work was supported by the French Ministry of Health, the Agence Nationale de la Recherche (ANR-08-GENO-033), French Foundation for Medical Research (FRM-DAL20051205066), the National Agency for Research (Netherlink: ANR-05-MRAR-009 01/NS2AD:ANR-08-GENO-033) and the E-Rare Joint Transnational Call for Projects on Rare Diseases (KLKIN).
References
Bitoun, E., Chavanas, S., Irvine, A.D., Lonie, L., Bodemer, C., Paradisi, M., Hamel-Teillac, D., Ansai, S., Mitsuhashi, Y., Taïeb, A., et al. (2002). Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J. Invest. Dermatol. 2, 352–361.10.1046/j.1523-1747.2002.01603.xSuche in Google Scholar PubMed
Bonnart, C., Deraison, C., Lacroix, M., Uchida, Y., Besson, C. Robin, A., Briot, A., Gonthier, M., Lamant, L., Dubus, P., et al. (2010). Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J. Clin. Invest. 120, 871–882.10.1172/JCI41440Suche in Google Scholar PubMed PubMed Central
Borgoño, C.A., Michael, I.P., Komatsu, N., Jayakumar, A., Kapadia, R., Clayman, G.L., Sotiropoulou, G., and Diamandis, E.P. (2007). A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J. Biol. Chem. 282, 3640–3652.10.1074/jbc.M607567200Suche in Google Scholar PubMed
Brattsand, M., Stefansson, K., Lundh, C., Haasum, Y., and Egelrud, T. (2005). A proteolytic cascade of kallikreins in the stratum corneum. J. Invest Dermatol. 124, 198–203.10.1111/j.0022-202X.2004.23547.xSuche in Google Scholar PubMed
Briot, A., Deraison C., Lacroix M., Bonnart C., Robin A., Besson C., Dubus P., and Hovnanian, A. (2009). Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton Syndrome. J. Exp. Med. 206, 1135–1147.10.1084/jem.20082242Suche in Google Scholar PubMed PubMed Central
Caubet, C., Jonca, N., Brattsand, M., Guerrin, M., Bernard, D., Schmidt, R., Egelrud, T., Simon, M., and Serre, G. (2004). Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Invest. Dermatol. 122, 1235–1244.10.1111/j.0022-202X.2004.22512.xSuche in Google Scholar PubMed
Chavanas, S., Bodemer, C., Rochat, A., Hamel-Teillac, D., Ali, M., Irvine, A.D., Bonafé, J.L., Wilkinson, J., Taïeb, A., Barrandon, Y., Harper, J.I., de Prost, Y. and Hovnanian, A. (2000). Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2, 141–142.10.1038/75977Suche in Google Scholar PubMed
Comel, M. (1949). Ichtyosis Linearis circumflexa. Dermatologica 98, 133–136.10.1159/000257290Suche in Google Scholar
De Veer, S., Furio, L., Harris, J.M., and Hovnanian, A. (2014). Proteases: common culprits in human skin disorders. Trends Mol. Med. 20, 166–178.10.1016/j.molmed.2013.11.005Suche in Google Scholar PubMed
Deraison, C., Bonnart, B., Lopez, F., Besson, C., Robinson, R., Jayakumar, A., Wagberg, F., Brattsand, M., Hachem, J.P., Leonardsson, G., et al. (2007). LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol. Biol. Cell 9, 3607–3619.10.1091/mbc.e07-02-0124Suche in Google Scholar PubMed PubMed Central
Descargues, P., Deraison, C., Bonnart, C., Kreft, M., Kishibe, M., Ishida-Yamamoto, A., Elias, P., Barrandon, Y., Zambruno, G., Sonnenberg, A., et al. (2005). Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat. Genet. 37, 56–65.10.1038/ng1493Suche in Google Scholar PubMed
Descargues, P., Deraison, C., Prost, C., Fraitag, S., Mazereeuw-Hautier, J., D’Alessio, M., Ishida-Yamamoto, A., Bodemer, C., Zambruno, G., and Hovnanian, A. (2006). Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin and chymotrypsinlike hyperactivity in Netherton syndrome. J. Invest. Dermatol. 126, 1622–1632.10.1038/sj.jid.5700284Suche in Google Scholar PubMed
Egelrud, T., Brattsand, M., Kreutzmann, P., Walden, M., Vitzithum, K., Marx, U.C., Forssman, W.G., and Magert, H.J. (2005). hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br. J. Dermatol. 153, 1200–1203.10.1111/j.1365-2133.2005.06834.xSuche in Google Scholar PubMed
Fartasch, M., Williams, M.L., and Elias, P.M. (1999). Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome. Arch. Dermatol. 135, 823–832.10.1001/archderm.135.7.823Suche in Google Scholar PubMed
Frateschi, S., Camerer, E., Crisante, G., Rieser, S., Membrez, M., Charles, R.P., Beermann, F., Stehle, J.C., Breiden, B., Sandhoff, K., et al. (2011). PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nat. Commun. 2, 161.10.1038/ncomms1162Suche in Google Scholar PubMed PubMed Central
Furio, L., de Veer, S., Jaillet, M., Briot, A., Robin, A., Deraison, C., and Hovnanian, A. (2014). Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. J. Exp. Med. 211, 499–513.10.1084/jem.20131797Suche in Google Scholar PubMed PubMed Central
Furio, L., Pampalakis, G., Iacovos, P., Michael, Nagy, A., Sotiropoulou, G., and Hovnanian, A. (2015). KLK5 inactivation reverses cutaneous hallmarks of Netherton syndrome. PLoS Genet. 11, 1–20.10.1371/journal.pgen.1005389Suche in Google Scholar PubMed PubMed Central
Hausser, I. and Anton-Lamprecht, I. (1996). Severe congenital generalized exfoliative erythroderma in newborns and infants: a possible sign of Netherton syndrome. Pediatr. Dermatol. 13, 183–199.10.1111/j.1525-1470.1996.tb01202.xSuche in Google Scholar PubMed
Judge, M.R., Morgan, G., and Harper, J.I. (1994). A clinical and immunological study of Netherton’s syndrome. Br. J. Dermatol. 131, 615–621.10.1111/j.1365-2133.1994.tb04971.xSuche in Google Scholar PubMed
Leclerc-Mercier, S., Bodemer, C., Furio, L., Hadj-Rabia, S., de Peufeilhoux, L., Weibel, L., Bursztejn, A.C., Bourrat, E., Ortonne, N., Molina, T.J., et al. (2016). Am. J. Dermatopathol. 38, 83–91.10.1097/DAD.0000000000000425Suche in Google Scholar PubMed
Netherton, E.W. (1958). A unique case of trichorrexis invaginata. Arch. Dermatol. 78, 483–487.10.1001/archderm.1958.01560100059009Suche in Google Scholar PubMed
Prassas I., Eissa A., Poda G., and Diamandis, E.P. (2015). Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat. Rev. 14, 183–202.10.1038/nrd4534Suche in Google Scholar
Raghunath, M., Tontsidou, L., Oji, V., Aufenvenne, K., Schürmeyer-Horst, F., Jayakumar, A., Ständer, H., Smolle, J., Clayman, G.L., and Traupe, H. (2004). SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. J. Invest. Dermatol. 3, 474–483.10.1111/j.0022-202X.2004.23220.xSuche in Google Scholar PubMed
Sales, K.U., Masedunskas, A., Bey, A.L., Rasmussen, A.L., Weigert, R., List, K., Szabo, R., Overbeek, P.A., and Bugge, T.H. (2010). Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat. Genet. 42, 676–683.10.1038/ng.629Suche in Google Scholar PubMed PubMed Central
Smith, D.L., Smith, J.G., Wong, S.W., and deShazo, R.D. (1995). Netherton’s syndrome. Br. J. Dermatol. 133, 153–154.10.1111/j.1365-2133.1995.tb02520.xSuche in Google Scholar PubMed
Sprecher, E., Amin, S., Nielsen, K., Pfendner, E., Uitto, J., Richard, G., Chavanas, S., DiGiovanna, J., Prendiville, J., Silverman, R., et al. (2001). The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J. Invest. Dermatol. 2, 179–187.10.1046/j.1523-1747.2001.01389.xSuche in Google Scholar PubMed
Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M., and Egelrud, T. (2008). Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18–25.10.1038/sj.jid.5700965Suche in Google Scholar PubMed
Stevanovic, D.V. (1969). Multiple defects of the hair shaft in Netherton’s disease. Association with ichthyosis linearis circumflexa. Br. J. Dermatol. 81, 851–857.10.1111/j.1365-2133.1969.tb15956.xSuche in Google Scholar PubMed
Traupe, H. (1989). The Ichthyosis: A Guide to Clinical Diagnosis, Genetic Counselling, and Therapy (Berlin Heidelberg: Springer-Verlag), pp. 45–78.10.1007/978-3-642-73650-6_5Suche in Google Scholar
Van Gysel, D., Koning, H., Baert, M.R.M., Savelkoul, H.F.J., Neijens, H.J., and Oranje, A.P. (2001).Clinico-immunological heterogeneity in Comel-Netherton syndrome. Dermatology 202, 99–107.10.1159/000051607Suche in Google Scholar PubMed
van Smeden, J., Janssens, M., Boiten, W.A., van Drongelen, V., Furio, L., Vreeken, R.J., Hovnanian, A., and Bouwstra, J.A. (2014). Intercellular skin barrier lipid composition and organization in Netherton syndrome patients. J. Invest. Dermatol. 5, 1238–1245.10.1038/jid.2013.517Suche in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
Artikel in diesem Heft
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine