title: Induction of phenotype modifying cytokines by FERMT1 mutations.
abstract: Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.
authors.affiliation: Department of Dermatology, University of Freiburg, Freiburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Heinemann
authors.forename: Yinghong
authors.initials: Y
authors.lastname: He
authors.forename: Elena
authors.initials: E
authors.lastname: Zimina
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.forename: Nadja
authors.initials: N
authors.lastname: Chmel
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kurz
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
mesh_terms: D000328:Adult; D001768:Blister / Q000235:genetics; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004820:Epidermolysis Bullosa / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010510:Periodontal Diseases / Q000235:genetics; D010641:Phenotype; D010787:Photosensitivity Disorders / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins