title: Cathepsin K is involved in development of psoriasis-like skin lesions through TLR-dependent Th17 activation.
abstract: Cathepsins (CTSs) are lysosomal cysteine proteases that play an important role in the turnover of intracellular proteins and extracellular proteins, such as the degradation of extracellular matrices and the processing of antigenic proteins. A CTS inhibitor, NC-2300, not only suppresses bone erosion by inhibition of cathepsin K (CTSK), but also ameliorates paw swelling at inflamed joints in adjuvant-induced arthritis in rats. It has been demonstrated that the amelioration of joint inflammation by NC-2300 is mediated by the downregulation of cytokine expression in dendritic cells, which are essential for Th17 activation. In this work, we studied the role for CTSs in the pathogenesis of psoriasis-like lesion in K5.Stat3C mice, a mouse model of psoriasis, in which Th17 contributes to lesion development similar to psoriasis. Psoriatic lesions expressed increased levels of Ctsk and Ctss mRNA compared with uninvolved skin and normal control skin. Similarly, the epidermis and dermis in K5.Stat3C mice demonstrated increased CTSK activities, which were sensitive to NC-2300. Topical treatment with NC-2300 significantly ameliorated 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like lesions in K5.Stat3C mice, and downregulated the expression of IL-12, IL-23, and Th17 cytokines. In vitro experiments revealed that TLR7 activation of bone marrow-derived myeloid dendritic cells led to increase in IL-23 at mRNA and protein levels, which were downregulated by NC-2300. These results suggest that CTSK plays a role in development of psoriatic lesions through TLR7-dependent Th17 polarization.
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.
authors.forename: Toshitake
authors.initials: T
authors.lastname: Hirai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sato
authors.forename: Mikiro
authors.initials: M
authors.lastname: Takaishi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Mayuko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Kamijima
authors.forename: John
authors.initials: J
authors.lastname: Digiovanni
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020405:Dermis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation; D004817:Epidermis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D053759:Interleukin-23; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D056657:Cathepsin K