KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome

English version České info

Netherton Syndrome (NS) is a severe form of ichthyosis characterized by desquamation, inflammation and multiple allergies, which can be life-threatening in infants. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. Current treatment options for this orphan disease are non-curative, focusing on the management of skin infections and the reduction of itching and pain. We developed a new murine model in which Klk5 and Spink5 were both inactivated to assess whether Klk5 loss is sufficient to reverse the NS phenotype in Spink5-/- mice. Here, we identified Klk5 as the major determinant of NS pathology. Solely by deleting Klk5 gene, we successfully demonstrated reversal of both desquamating and inflammatory manifestations of NS. These were accompanied by drastic improvement of skin barrier defect, restoration of normal epidermal differentiation and epidermal ultrastructure. Our data identified KLK5 as a new target for drug development in NS, thus setting the foundation for designing the first targeted therapy against NS. NS shares several biological features and proteolytic unbalance with other inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis. An increasing population suffers from these frequent skin diseases. Our findings could therefore have implication in the treatment of these common and disabling diseases.

Vyšlo v časopise: KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005389
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005389

Souhrn

Zdroje

1. Simpson CL, Patel DM, Green KJ (2011) Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol 12: 565–580. doi: 10.1038/nrm3175 21860392

2. Fuchs E (2007) Scratching the surface of skin development. Nature 445: 834–842. 17314969

3. Netherton EW (1958) "A unique case of trichorrhexis nodosa: bamboo hairs. AMA Arch Derm 78: 483–487. 13582191

4. Comel M (1949) Ichthyosis Linearis circumflexa. Dermatologica 98: 133–136.

5. Hovnanian A (2012) Netherton syndrome: new advances in clinic, disease mechanism and treatment. Expert review 7: 81–92.

6. Ong C, Harper J (2006) Netherton's syndrome. In: Harper J, Orange A, Prose N, editors. Textbook of pediatric Dermatology. Second ed. Turin, Italy: Blackwell. pp. 1359–1366.

7. Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, et al. (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25: 141–142. 10835624

8. Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, et al. (2007) LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 18: 3607–3619. 17596512

9. Fortugno P, Bresciani A, Paolini C, Pazzagli C, El Hachem M, et al. (2011) Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. J Invest Dermatol 131: 2223–2232. doi: 10.1038/jid.2011.174 21697885

10. Egelrud T, Brattsand M, Kreutzmann P, Walden M, Vitzithum K, et al. (2005) hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 153: 1200–1203. 16307658

11. Borgoño CA, Michael IP, Komatsu N, Jayakumar A, Kapadia R, et al. (2007) A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 282: 3640–3652. 17158887

12. Descargues P, Deraison C, Bonnart C, Kreft M, Kishibe M, et al. (2005) Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 37: 56–65. 15619623

13. Hewett DR, Simons AL, Mangan NE, Jolin HE, Green SM, et al. (2005) Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome. Hum Mol Genet 14: 335–346. 15590704

14. Yang T, Liang D, Koch PJ, Hohl D, Kheradmand F, et al. (2004) Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. Genes Dev 18: 2354–2358. 15466487

15. Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, et al. (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206: 1135–1147. doi: 10.1084/jem.20082242 19414552

16. Briot A, Lacroix M, Robin A, Steinhoff M, Deraison C, et al. (2010) Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J Invest Dermatol 130: 2736–2742. doi: 10.1038/jid.2010.233 20703245

17. Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, et al. (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. 15140227

18. Ovaere P, Lippens S, Vandenabeele P, Declercq W (2009) The emerging roles of serine protease cascades in the epidermis. Trends Biochem Sci 34: 453–463. doi: 10.1016/j.tibs.2009.08.001 19726197

19. Miyai M, Matsumoto Y, Yamanishi H, Yamamoto-Tanaka M, Tsuboi R, et al. (2014) Keratinocyte-Specific Mesotrypsin Contributes to the Desquamation Process via Kallikrein Activation and LEKTI Degradation. J Invest Dermatol.

20. Sales KU, Masedunskas A, Bey AL, Rasmussen AL, Weigert R, et al. (2010) Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 42: 676–683. doi: 10.1038/ng.629 20657595

21. de Veer SJ, Furio L, Harris JM, Hovnanian A (2014) Proteases and proteomics: cutting to the core of human skin pathologies. Proteomics Clin Appl 8: 389–402. doi: 10.1002/prca.201300081 24677727

22. Bonnart C, Deraison C, Lacroix M, Uchida Y, Besson C, 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. doi: 10.1172/JCI41440 20179351

23. Furio L, de Veer S, Jaillet M, Briot A, Robin A, et al. (2014) Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. J Exp Med 211: 499–513. doi: 10.1084/jem.20131797 24534191

24. de Veer SJ, Swedberg JE, Parker EA, Harris JM (2012) Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14. Biol Chem 393: 331–341. doi: 10.1515/bc-2011-250 22505516

25. de Veer SJ, Ukolova SS, Munro CA, Swedberg JE, Buckle AM, et al. (2013) Mechanism-based selection of a potent kallikrein-related peptidase 7 inhibitor from a versatile library based on the sunflower trypsin inhibitor SFTI-1. Biopolymers 100: 510–518. doi: 10.1002/bip.22231 24078181

26. Brattsand M, Egelrud T (1999) Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J Biol Chem 274: 30033–30040. 10514489

27. Suzuki Y, Nomura J, Hori J, Koyama J, Takahashi M, et al. (1993) Detection and characterization of endogenous protease associated with desquamation of stratum corneum. Arch Dermatol Res 285: 372–377. 8215586

28. Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-Hautier J, et al. (2006) Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J Invest Dermatol 126: 1622–1632. 16628198

29. Fartasch M, Williams ML, Elias PM (1999) Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications. Arch Dermatol 135: 823–832. 10411158

30. Hausser I, Anton-Lamprecht I (1996) Severe congenital generalized exfoliative erythroderma in newborns and infants: a possible sign of Netherton syndrome. Pediatr Dermatol 13: 183–199. 8806118

31. Yamasaki K, Schauber J, Coda A, Lin H, Dorschner RA, et al. (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. Faseb J 20: 2068–2080. 17012259

32. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, et al. (2007) Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 13: 975–980. 17676051

33. Homey B, Zlotnik A (1999) Chemokines in allergy. Curr Opin Immunol 11: 626–634. 10631546

34. Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, et al. (2008) Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159: 1092–1102. doi: 10.1111/j.1365-2133.2008.08769.x 18684158

35. Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, et al. (2005) IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 174: 3695–3702. 15749908

36. Fischer J, Meyer-Hoffert U (2013) Regulation of kallikrein-related peptidases in the skin—from physiology to diseases to therapeutic options. Thromb Haemost 110: 442–449. doi: 10.1160/TH12-11-0836 23446429

37. Sotiropoulou G, Pampalakis G (2010) Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation. Biol Chem 391: 321–331. doi: 10.1515/BC.2010.036 20180637

38. Sakabe J, Yamamoto M, Hirakawa S, Motoyama A, Ohta I, et al. (2013) Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes. J Biol Chem 288: 17179–17189. doi: 10.1074/jbc.M113.476820 23629652

39. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, et al. (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3: 673–680. 12055625

40. Sun JD, Linden KG (2006) Netherton syndrome: a case report and review of the literature. Int J Dermatol 45: 693–697. 16796630

41. Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, et al. (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129: 1892–1908. doi: 10.1038/jid.2009.133 19494826

42. Takai T, Ikeda S (2011) Barrier dysfunction caused by environmental proteases in the pathogenesis of allergic diseases. Allergol Int 60: 25–35. doi: 10.2332/allergolint.10-RAI-0273 21173566

43. Angelova-Fischer I, Fernandez IM, Donnadieu MH, Bulfone-Paus S, Zillikens D, et al. (2010) Injury to the stratum corneum induces in vivo expression of human thymic stromal lymphopoietin in the epidermis. J Invest Dermatol 130: 2505–2507. doi: 10.1038/jid.2010.143 20555350

44. Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S (2014) Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 71: 141–150. doi: 10.1016/j.jaad.2013.12.036 24655820

45. Guttman-Yassky E, Dhingra N, Leung DY (2013) New era of biologic therapeutics in atopic dermatitis. Expert Opin Biol Ther 13: 549–561. doi: 10.1517/14712598.2013.758708 23323893

46. Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, et al. (2013) Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 132: 361–370. doi: 10.1016/j.jaci.2013.04.046 23777851

47. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y (2008) Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 128: 2625–2630. doi: 10.1038/jid.2008.111 18432274

48. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203: 2271–2279. 16982811

49. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE, et al. (2009) Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol 129: 2175–2183. doi: 10.1038/jid.2009.65 19295614

50. Tanaka M, Hadjantonakis AK, Vintersten K, Nagy A (2009) Aggregation chimeras: combining ES cells, diploid, and tetraploid embryos. Methods Mol Biol 530: 287–309. doi: 10.1007/978-1-59745-471-1_15 19266342

51. Hardman MJ, Sisi P, Banbury DN, Byrne C (1998) Patterned acquisition of skin barrier function during development. Development 125: 1541–1552. 9502735