TY - JOUR

T1 - Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice

AU - Thyssen, Jacob P.

AU - Jakasa, Ivone

AU - Riethmüller, Christoph

AU - Schön, Michael P.

AU - Braun, Andrea

AU - Haftek, Marek

AU - Fallon, Padraic G.

AU - Wróblewski, Jacek

AU - Jakubowski, Hieronim

AU - Eckhart, Leopold

AU - Declercq, Wim

AU - Koppes, Sjors

AU - Engebretsen, Kristiane A.

AU - Bonefeld, Charlotte

AU - Irvine, Alan D.

AU - Keita-Alassane, Sokhna

AU - Simon, Michel

AU - Kawasaki, Hiroshi

AU - Kubo, Akiharu

AU - Amagai, Masayuki

AU - Matsui, Takeshi

AU - Kezic, Sanja

PY - 2020

Y1 - 2020

N2 - Abundant corneocyte surface protrusions, observed in patients with atopic dermatitis with filaggrin loss-of-function mutations, are inversely associated with levels of natural moisturizing factors (NMFs) in the stratum corneum. To dissect the etiological role of NMFs and filaggrin deficiency in surface texture alterations, we examined mouse models with genetic deficiencies in the synthesis or degradation of filaggrin monomers for NMFs, cell stiffness (elastic modulus) and corneocyte surface protrusion density (dermal texture index). Five neonatal and adult mouse models carrying inactivating mutations of SASPase (Sasp−/−), filaggrin (Flgft/ft and Flg−/−), filaggrin-hornerin (FlgHrnr−/−), and bleomycin hydrolase (Blmh−/−) were investigated. Sasp−/− and Flg−/− were on the hairless mouse background. Atomic force microscopy was used to determine elastic modulus and dermal texture index. Corneocytes of each neonatal as well as hairless adult knockout mouse exhibited an increased number of protrusions and decreased elastic modulus. In these mice, NMFs were reduced except for Sasp−/−. Dermal texture index was inversely correlated with NMFs and elastic modulus. Our findings demonstrate that any filaggrin-NMF axis deficiency can affect corneocyte mechanical properties in mice and likely in humans. Differences in NMFs and corneocyte surface texture between neonatal and adult as well as hairless and hairy mice emphasize the need for carefully selecting the most appropriate animal models for studies.

AB - Abundant corneocyte surface protrusions, observed in patients with atopic dermatitis with filaggrin loss-of-function mutations, are inversely associated with levels of natural moisturizing factors (NMFs) in the stratum corneum. To dissect the etiological role of NMFs and filaggrin deficiency in surface texture alterations, we examined mouse models with genetic deficiencies in the synthesis or degradation of filaggrin monomers for NMFs, cell stiffness (elastic modulus) and corneocyte surface protrusion density (dermal texture index). Five neonatal and adult mouse models carrying inactivating mutations of SASPase (Sasp−/−), filaggrin (Flgft/ft and Flg−/−), filaggrin-hornerin (FlgHrnr−/−), and bleomycin hydrolase (Blmh−/−) were investigated. Sasp−/− and Flg−/− were on the hairless mouse background. Atomic force microscopy was used to determine elastic modulus and dermal texture index. Corneocytes of each neonatal as well as hairless adult knockout mouse exhibited an increased number of protrusions and decreased elastic modulus. In these mice, NMFs were reduced except for Sasp−/−. Dermal texture index was inversely correlated with NMFs and elastic modulus. Our findings demonstrate that any filaggrin-NMF axis deficiency can affect corneocyte mechanical properties in mice and likely in humans. Differences in NMFs and corneocyte surface texture between neonatal and adult as well as hairless and hairy mice emphasize the need for carefully selecting the most appropriate animal models for studies.

U2 - 10.1016/j.jid.2019.07.716

DO - 10.1016/j.jid.2019.07.716

M3 - Journal article

C2 - 31479664

AN - SCOPUS:85074345710

VL - 140

SP - 615

EP - 623

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 3

ER -