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Aberrant serine protease activities in atopic dermatitis

  • Shin Morizane
    Correspondence
    Correspondence to: Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2–5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
    Affiliations
    Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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  • Ko Sunagawa
    Affiliations
    Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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  • Hayato Nomura
    Affiliations
    Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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  • Mamoru Ouchida
    Affiliations
    Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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      Highlights

      • Trypsin- and chymotrypsin-like serine protease activities are enhanced in AD lesions.
      • Many KLKs expression is upregulated in AD lesions.
      • LEKTI function is decreased in some AD patients with SNPs E420K and D386N of SPINK5.
      • Aberrant serine protease activities disrupt the normal epidermal barrier function.
      • Some KLKs can activate PAR2 in epidermal keratinocytes and peripheral nerves

      Abstract

      Atopic dermatitis (AD) is a chronic inflammatory skin disease; the three major factors responsible for AD, i.e., epidermal barrier dysfunction, allergic inflammation, and itching, interact with each other to form a pathological condition. Excessive protease activities are characteristic abnormalities that affect the epidermal barrier in patients with AD. In normal skin, epidermal serine protease activities are controlled by kallikrein-related peptidases (KLKs) and their inhibitors, including lympho-epithelial Kazal-type-related inhibitor (LEKTI). In AD lesions, KLKs are excessively expressed, which results in the enhancement of epidermal serine protease activities and facilitates the invasion by allergens and microorganisms. In addition, some KLKs can activate protease-activated receptor 2 (PAR2) in epidermal keratinocytes and peripheral nerves, resulting in the induction of inflammation and itching. Furthermore, in AD patients with single nucleotide polymorphism (SNP) such as E420K and D386N of SPINK5 which encodes LEKTI, LEKTI function is attenuated, resulting in the activation of KLKs and easy invasion by allergens and microorganisms. Further analysis is needed to elucidate the detailed mechanism underlying the control of serine protease activities, which may lead to the development of new therapeutic and prophylactic agents for AD.

      Abbreviations:

      AD (Atopic dermatitis), KLKs (kallikrein-related peptidases), LEKTI (lymphoepithelial Kazal-type-related inhibitor), PAR2 (protease-activated receptor 2), NS (Netherton syndrome)

      Keywords

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      References

        • Kabashima K.
        New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity.
        J. Dermatol. Sci. 2013; 70: 3-11
        • McAleer M.A.
        • Irvine A.D.
        The multifunctional role of filaggrin in allergic skin disease.
        J. Allergy Clin. Immunol. 2013; 131: 280-291
        • Palmer C.N.
        • Irvine A.D.
        • Terron-Kwiatkowski A.
        • Zhao Y.
        • Liao H.
        • Lee S.P.
        • et al.
        Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
        Nat. Genet. 2006; 38: 441-446
        • Song C.W.
        • Tabachnick J.
        • McCarron Jr, D.J.
        A trypsin-like protease in guinea pig skin.
        Experientia. 1969; 25: 1063-1064
        • Rajka G.
        Experimental pruritus in the unaffected skin of patients with different itching dermatoses.
        Acta Derm. Venereol. 1970; 50: 270-272
        • Voegeli R.
        • Rawlings A.V.
        • Breternitz M.
        • Doppler S.
        • Schreier T.
        • Fluhr J.W.
        Increased stratum corneum serine protease activity in acute eczematous atopic skin.
        Br. J. Dermatol. 2009; 161: 70-77
        • Nomura H.
        • Suganuma M.
        • Takeichi T.
        • Kono M.
        • Isokane Y.
        • Sunagawa K.
        • et al.
        Multifaceted analyses of epidermal serine protease activity in patients with atopic dermatitis.
        Int J. Mol. Sci. 2020; 21
        • Nomura H.
        • Kawakami Y.
        • Yasutomi Y.
        • Morizane S.
        Two atopic dermatitis patients in whom dupilumab improved aberrant epidermal protease activities.
        J. Cutan. Immunol. Allergy. 2019; 2: 87-88
        • Kraut H.
        • Frey E.
        • Werle E.
        Der Nachweis eines Kreislaufhormon in der pankreasdruse.
        Hoppe-Seyler Z. Physiol. Chem. 1930; 189: 97-106
        • Yousef G.M.
        • Diamandis E.P.
        The new human tissue kallikrein gene family: structure, function, and association to disease.
        Endocr. Rev. 2001; 22: 184-204
        • Kalinska M.
        • Meyer-Hoffert U.
        • Kantyka T.
        • Potempa J.
        Kallikreins - The melting pot of activity and function.
        Biochimie. 2016; 122: 270-282
        • Caubet C.
        • Jonca N.
        • Brattsand M.
        • Guerrin M.
        • Bernard D.
        • Schmidt R.
        • et al.
        Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.
        J. Invest Dermatol. 2004; 122: 1235-1244
        • Nylander-Lundqvist E.
        • Egelrud T.
        Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro.
        Acta Derm. Venereol. 1997; 77: 203-206
        • Cork M.J.
        • Robinson D.A.
        • Vasilopoulos Y.
        • Ferguson A.
        • Moustafa M.
        • MacGowan A.
        • et al.
        New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions.
        J. Allergy Clin. Immunol. 2006; 118 (quiz 22-23): 3-21
        • Rippke F.
        • Schreiner V.
        • Doering T.
        • Maibach H.I.
        Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus.
        Am. J. Clin. Dermatol. 2004; 5: 217-223
        • Komatsu N.
        • Saijoh K.
        • Kuk C.
        • Liu A.C.
        • Khan S.
        • Shirasaki F.
        • et al.
        Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients.
        Exp. Dermatol. 2007; 16: 513-519
        • Brattsand M.
        • Egelrud T.
        Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation.
        J. Biol. Chem. 1999; 274: 30033-30040
        • Bonnart C.
        • Deraison C.
        • Lacroix M.
        • Uchida Y.
        • Besson C.
        • Robin A.
        • et al.
        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. 2010; 120: 871-882
        • Sakabe J.
        • Yamamoto M.
        • Hirakawa S.
        • Motoyama A.
        • Ohta I.
        • Tatsuno K.
        • et al.
        Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes.
        J. Biol. Chem. 2013; 288: 17179-17189
        • Yamasaki K.
        • Schauber J.
        • Coda A.
        • Lin H.
        • Dorschner R.A.
        • Schechter N.M.
        • et al.
        Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin.
        FASEB J. 2006; 20: 2068-2080
        • Eissa A.
        • Diamandis E.P.
        Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions.
        Biol. Chem. 2008; 389: 669-680
        • Bin L.
        • Kim B.E.
        • Hall C.F.
        • Leach S.M.
        • Leung D.Y.
        Inhibition of transcription factor specificity protein 1 alters the gene expression profile of keratinocytes leading to upregulation of kallikrein-related peptidases and thymic stromal lymphopoietin.
        J. Invest Dermatol. 2011; 131: 2213-2222
        • Kamata Y.
        • Yamamoto M.
        • Kawakami F.
        • Tsuboi R.
        • Takeda A.
        • Ishihara K.
        • et al.
        Bleomycin hydrolase is regulated biphasically in a differentiation- and cytokine-dependent manner: relevance to atopic dermatitis.
        J. Biol. Chem. 2011; 286: 8204-8212
        • Morizane S.
        • Yamasaki K.
        • Kajita A.
        • Ikeda K.
        • Zhan M.
        • Aoyama Y.
        • et al.
        TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis.
        J. Allergy Clin. Immunol. 2012; 130 (e251): 259-261
        • Morizane S.
        • Yamasaki K.
        • Kabigting F.D.
        • Gallo R.L.
        Kallikrein expression and cathelicidin processing are independently controlled in keratinocytes by calcium, vitamin D(3), and retinoic acid.
        J. Invest Dermatol. 2010; 130: 1297-1306
        • Briot A.
        • Deraison C.
        • Lacroix M.
        • Bonnart C.
        • Robin A.
        • Besson C.
        • et al.
        Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.
        J. Exp. Med. 2009; 206: 1135-1147
        • Jang H.
        • Matsuda A.
        • Jung K.
        • Karasawa K.
        • Matsuda K.
        • Oida K.
        • et al.
        Skin pH is the master switch of kallikrein 5-mediated skin barrier destruction in a murine atopic dermatitis model.
        J. Invest Dermatol. 2015;
        • Buhl T.
        • Ikoma A.
        • Kempkes C.
        • Cevikbas F.
        • Sulk M.
        • Buddenkotte J.
        • et al.
        Protease-activated receptor-2 regulates neuro-epidermal communication in atopic dermatitis.
        Front Immunol. 2020; 11: 1740
        • Steinhoff M.
        • Neisius U.
        • Ikoma A.
        • Fartasch M.
        • Heyer G.
        • Skov P.S.
        • et al.
        Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.
        J. Neurosci. 2003; 23: 6176-6180
        • Andoh T.
        • Tsujii K.
        • Kuraishi Y.
        Increase in pruritogenic kallikrein 5 in the skin of NC mice with chronic dermatitis.
        Exp. Dermatol. 2015; 24: 978-980
        • Oikonomopoulou K.
        • Hansen K.K.
        • Saifeddine M.
        • Tea I.
        • Blaber M.
        • Blaber S.I.
        • et al.
        Proteinase-activated receptors, targets for kallikrein signaling.
        J. Biol. Chem. 2006; 281: 32095-32112
        • Zhu Y.
        • Underwood J.
        • Macmillan D.
        • Shariff L.
        • O’Shaughnessy R.
        • Harper J.I.
        • et al.
        Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity.
        J. Allergy Clin. Immunol. 2017; 140 (e1315): 1310-1322
        • Furio L.
        • de Veer S.
        • Jaillet M.
        • Briot A.
        • Robin A.
        • Deraison C.
        • et al.
        Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome.
        J. Exp. Med. 2014; 211: 499-513
        • Lundstrom A.
        • Egelrud T.
        Stratum corneum chymotryptic enzyme: a proteinase which may be generally present in the stratum corneum and with a possible involvement in desquamation.
        Acta Derm. Venereol. 1991; 71: 471-474
        • Hansson L.
        • Stromqvist M.
        • Backman A.
        • Wallbrandt P.
        • Carlstein A.
        • Egelrud T.
        Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase.
        J. Biol. Chem. 1994; 269: 19420-19426
        • Igawa S.
        • Kishibe M.
        • Minami-Hori M.
        • Honma M.
        • Tsujimura H.
        • Ishikawa J.
        • et al.
        Incomplete KLK7 secretion and upregulated lekti expression underlie hyperkeratotic stratum corneum in atopic dermatitis.
        J. Invest Dermatol. 2017; 137: 449-456
        • Hansson L.
        • Backman A.
        • Ny A.
        • Edlund M.
        • Ekholm E.
        • Ekstrand Hammarstrom B.
        • et al.
        Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis.
        J. Invest Dermatol. 2002; 118: 444-449
        • Guo C.J.
        • Mack M.R.
        • Oetjen L.K.
        • Trier A.M.
        • Council M.L.
        • Pavel A.B.
        • et al.
        Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation.
        J. Invest Dermatol. 2020; 140 (e1244): 1244-1252
        • Stefansson K.
        • Brattsand M.
        • Roosterman D.
        • Kempkes C.
        • Bocheva G.
        • Steinhoff M.
        • et al.
        Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases.
        J. Invest Dermatol. 2008; 128: 18-25
        • Vasilopoulos Y.
        • Cork M.J.
        • Murphy R.
        • Williams H.C.
        • Robinson D.A.
        • Duff G.W.
        • et al.
        Genetic association between an AACC insertion in the 3′UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.
        J. Invest Dermatol. 2004; 123: 62-66
        • Vasilopoulos Y.
        • Sharaf N.
        • di Giovine F.
        • Simon M.
        • Cork M.J.
        • Duff G.W.
        • et al.
        The 3′-UTR AACCins5874 in the stratum corneum chymotryptic enzyme gene (SCCE/KLK7), associated with atopic dermatitis; causes an increased mRNA expression without altering its stability.
        J. Dermatol. Sci. 2011; 61: 131-133
        • Hubiche T.
        • Ged C.
        • Benard A.
        • Leaute-Labreze C.
        • McElreavey K.
        • de Verneuil H.
        • et al.
        Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort.
        Acta Derm. Venereol. 2007; 87: 499-505
        • Eissa A.
        • Amodeo V.
        • Smith C.R.
        • Diamandis E.P.
        Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade.
        J. Biol. Chem. 2011; 286: 687-706
        • Williams M.R.
        • Nakatsuji T.
        • Sanford J.A.
        • Vrbanac A.F.
        • Gallo R.L.
        Staphylococcus aureus induces increased serine protease activity in keratinocytes.
        J. Invest Dermatol. 2017; 137: 377-384
        • Yasuda T.
        • Fukada T.
        • Nishida K.
        • Nakayama M.
        • Matsuda M.
        • Miura I.
        • et al.
        Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis.
        J. Clin. Invest. 2016; 126: 2064-2076
        • Billi A.C.
        • Ludwig J.E.
        • Fritz Y.
        • Rozic R.
        • Swindell W.R.
        • Tsoi L.C.
        • et al.
        KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease.
        J. Clin. Invest. 2020; 130: 3151-3157
        • Hovnanian A.
        Netherton syndrome: skin inflammation and allergy by loss of protease inhibition.
        Cell Tissue Res. 2013; 351: 289-300
        • Descargues P.
        • Deraison C.
        • Bonnart C.
        • Kreft M.
        • Kishibe M.
        • Ishida-Yamamoto A.
        • et al.
        Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.
        Nat. Genet. 2005; 37: 56-65
        • Fortugno P.
        • Furio L.
        • Teson M.
        • Berretti M.
        • El Hachem M.
        • Zambruno G.
        • et al.
        The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis.
        Hum. Mol. Genet. 2012; 21: 4187-4200
        • Ramesh K.
        • Matta S.A.
        • Chew F.T.
        • Mok Y.K.
        Exonic mutations associated with atopic dermatitis disrupt lympho-epithelial Kazal-type related inhibitor action and enhance its degradation.
        Allergy. 2020; 75: 403-411
        • Kobashi M.
        • Morizane S.
        • Sugimoto S.
        • Sugihara S.
        • Iwatsuki K.
        Expression of serine protease inhibitors in epidermal keratinocytes is increased by calcium but not 1,25-dihydroxyvitamin D3 or retinoic acid.
        Br. J. Dermatol. 2017; 176: 1525-1532
        • Sugihara S.
        • Sugimoto S.
        • Tachibana K.
        • Kobashi M.
        • Nomura H.
        • Miyake T.
        • et al.
        TNF-alpha and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes.
        J. Dermatol. Sci. 2019; 96: 26-32

      Biography

      Dr. Shin Morizane is a Professor & Chairman of Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan. He obtained his M.D. and Ph.D. in 2000 and 2006, respectively. He studied as a postdoctoral fellow at Division of Dermatology, University of California, San Diego, in the United States (Prof. Richard Gallo) from 2007 to 2009. His research interests include epidermal serine protease activities and innate immunity in the skin.