Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice

Kawasaki, Hiroshi; Nagao, Keisuke; Kubo, Akiharu; Hata, Tsuyoshi; Shimizu, Atsushi; Mizuno, Hideaki; Yamada, Taketo; Amagai, Masayuki

doi:10.1016/j.jaci.2012.01.068

Cited by 273 publications

(249 citation statements)

References 43 publications

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“…Furthermore, elevation of pro-inflammatory cytokines in filaggrin-related AE represents a late event, possibly resulting from a defective barrier and the responding immune system (Brown and McLean, 2012;Kezic et al, 2012;Kou et al, 2012). In contrast to prediction, deletion of filaggrin in mice does not affect survival or cause an elevated trans-epidermal water loss, but results in enhanced responses in contact hypersensitivity (Kawasaki et al, 2012). The unexpectedly mild phenotype arising from complete loss of filaggrin leads to questions about the involvement of KRT1.…”

Section: Discussionmentioning

confidence: 99%

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

Roth

Kumar²,

Beer

et al. 2012

Journal of Cell Science

144

151

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SummaryKeratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and the S100A8 and S100A9 proteins, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1 2/2 mice. IL-18 release was keratinocyte-autonomous, KRT1 and caspase-1 dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema and psoriasis, but different from Krt5 deficiency and epidermolysis bullosa simplex. Our data suggest a functional link between KRT1 and human inflammatory skin diseases.

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Section: Discussionmentioning

confidence: 99%

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

Roth

Kumar²,

Beer

et al. 2012

Journal of Cell Science

144

151

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“…in mice null for Pig-a, CAP1/Prss8, caspase-14, matriptase/MT-SP1 or Flg mice), but it was linked to either a blockade in the processing of (pro)Flg or a total absence of proFlg synthesis (Denecker et al, 2007;Hara-Chikuma et al, 2004;Kawasaki et al, 2012;Leyvraz et al, 2005;List et al, 2003). By contrast, an accumulation of Flg monomers was described in the case of Spink5 R820X/R820X mice and of mice overexpressing claudin 6 (Hewett et al, 2005;Turksen and Troy, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, Flg is the main source of free amino acids and derivatives, and thus considered to play a crucial role in stratum corneum hydration. However, recent findings using Flg 2/2 mice, which exhibited a marked decrease in NMF values but normal TEWL and stratum corneum hydration, incite to carefully interpret the relations between Flg and hydration (Kawasaki et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Mice deficient for the epidermal Dermokine β and γ display transient cornification defects

Leclerc

Huchenq

Kežić

et al. 2014

Journal of Cell Science

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Expression of the human dermokine gene (DMKN) leads to the production of four dermokine isoform families. The secreted a, b and c isoforms have an epidermis-restricted expression pattern, with Dmkn b and c being specifically expressed by the granular keratinocytes. The d isoforms are intracellular and ubiquitous. Here, we performed an in-depth characterization of Dmkn expression in mouse skin and found an expression pattern that was less complex than in humans. In particular, mRNA coding for the d family were absent. Homozygous mice null for the Dmkn b and c isoforms had no obvious phenotype but only a temporary scaly skin during the first week of life. The pups null for the Dmkn b and c isoforms had smaller keratohyalin granules and their cornified envelopes were more sensitive to mechanical stress. At the molecular level, amounts of profilaggrin and filaggrin monomers were reduced whereas amino acid components of the natural moisturizing factor were increased. In addition, the electrophoretic mobility of involucrin was modified, suggesting post-translational modifications. Finally, the mice null for the Dmkn b and c isoforms strongly overexpressed Dmkn a. These data are evocative of compensatory mechanisms relevant to the temporary phenotype. Overall, we improved the knowledge of Dmkn expression in mouse and highlighted a role for Dmkn b and c in cornification.

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“…8 Both the flaky tail mouse (which carries a natural mutation virtually ablating all FLG expression 9 ) and FLG knockout mice exhibit enhanced percutaneous antigen transfer and allergen/ irritant-induced AE-like inflammatory responses. 10,11 These models support a primary role for FLG and highlight the importance of a functional cutaneous barrier in AE disease pathogenesis.…”

mentioning

confidence: 60%

“…The human and murine FLG sequences lack homology, 17 and murine models do not display the heterozygote phenotype typical of most patients with AE. 10,11 Consequently, the precise molecular changes occurring directly as a result of FLG loss are relatively unknown.…”

mentioning

confidence: 99%

127 Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema

Elias¹,

Long

Newman

et al. 2016

Journal of Investigative Dermatology

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GRAPHICAL ABSTRACTBackground: Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood. Objectives: We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skinequivalent (LSE) models and validate findings in skin of patients with AE. Methods: Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG])

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Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice

Cited by 273 publications

References 43 publications

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

Mice deficient for the epidermal Dermokine β and γ display transient cornification defects

127 Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema

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