Induction of Phenotype Modifying Cytokines by FERMT1 Mutations

Anja Heinemann (1) , Yinghong He (1) , Elena Zimina (1) , Melanie Boerries (2) , Hauke Busch (2) , Nadja Chmel (1) , Thorsten Kurz (3) , Leena Bruckner-Tuderman (1, 2) , Cristina Has (4)

1 Dermatology
2 FRIAS - Freiburg Institute for Advanced Studies
3 Center for Systems Biology
4 Dermatology

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.

Mots clés: Life Sciences

Anja Heinemann, Yinghong He, Elena Zimina, Melanie Boerries, Hauke Busch, et al.. Induction of Phenotype Modifying Cytokines by FERMT1 Mutations. Human Mutation, 2011, 32 (4), pp.397. ⟨10.1002/humu.21449⟩. ⟨hal-00618181⟩