title: Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis.
abstract: Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD.
authors: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan. Electronic address: igasato@asahikawa-med.ac.jp.
authors: Satomi
authors: S
authors: Igawa
authors: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors: Mari
authors: M
authors: Kishibe
authors: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors: Masako
authors: M
authors: Minami-Hori
authors: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors: Masaru
authors: M
authors: Honma
authors: Analytical Science Research, Kao Corporation, Haga, Ichikai, Tochigi, Japan.
authors: Hisashi
authors: H
authors: Tsujimura
authors: Biological Science Research, Kao Corporation, Haga, Ichikai, Tochigi, Japan.
authors: Junko
authors: J
authors: Ishikawa
authors: Biological Science Research, Kao Corporation, Haga, Ichikai, Tochigi, Japan.
authors: Tsutomu
authors: T
authors: Fujimura
authors: Department of Dermatology, Ehime University Graduate School of Medicine, Toon, Japan.
authors: Masamoto
authors: M
authors: Murakami
authors: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors: Akemi
authors: A
authors: Ishida-Yamamoto
mesh_terms: D003876:Dermatitis, Atopic / Q000150:complications*; D003896:Desmosomes / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000502:physiology*; D007642:Keratosis / Q000209:etiology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000502:physiology*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C082472:KLK7 protein, human; D007610:Kallikreins