J Allergy Clin Immunol. 2013 Apr;131(4):1094-102.

Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.

Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, Méchin MC, Hansmann B, Rodriguez E, Weindinger S, Schmitt AM, Serre G, Paul C, Simon M.

UMR5165 CNRS, U1056 INSERM, University of Toulouse, Department of Dermatology, University Hospital of Toulouse, Toulouse, France.

 

Abstract

BACKGROUND:

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG).

OBJECTIVES:

We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD.

METHODS:

An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25.

RESULTS:

Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels.

CONCLUSION:

The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction.

Copyright © 2013 American Academy of Allergy, Asthma & Immunology.

PMID: 23403047

 

The paper explained:

PROBLEM:

Atopic dermatitis (AD) is a chronic inflammatory skin disease clinically characterized by a disturbed epidermal barrier (increased permeability, decreased pH, structural and biochemical abnormalities). In a subset (1/3 at a maximum) of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG). FLG is a member of the S100-fused type protein (SFTP) family. It is considered as a key protein for the function and properties of the outermost layer of the epidermis, the stratum corneum. However, in patients who are not carriers of such mutations there must be additional mechanisms.

RESULTS:

We analysed biopsies of the lesional and non-lesional skin from 73 well characterized AD adult patients, and of healthy skin from 73 matched controls for the expression of FLG and of two other SFTPs named FLG2 and hornerin.  FLG2 and hornerin are closely related to FLG and play similar roles in the epidermal barrier function. We showed that  i) as compared to normal skin, FLG expression is reduced in both the lesional and non-lesional skin of AD patients, irrespective of their FLG genotype; ii) the proFLG (the FLG high molecular weight precursor) and/or FLG proteolytic processing is altered in the lesional and non-lesional skin of patients without FLG nonsense mutations; iii) the expression of hornerin and FLG2 is also reduced in both the lesional and non-lesional skin of the patients, as compared to controls; iv) pro-inflammatory cytokines down-regulate the expression of the three proteins in cultured primary keratinocytes.

IMPACT:

Our present results bring key findings allowing the complex pathophysiology of AD to be unraveled. They demonstrate that defects in the pro(FLG) processing, and pro-inflammatory cytokines participate, beside FLG gene nonsense mutations, to the reduced amount of FLG in the upper layer of the epidermis in AD patients. They indicate that the stratum corneum of lesional but also that of clinically unaffected skin of AD patients are abnormal and probably allow intra-epidermal penetration of environmental antigens and irritants, initiating the inflammatory response. In turn, pro-inflammatory cytokines may further reduce the expression of stratum corneum proteins involved in the epidermal barrier function, perpetuating the disease.

Clinical implications: treatment of atopic dermatitis patients should aim to 1) repair the defective epidermal barrier on both the lesional and non-lesional skin, and 2) inhibit the deleterious effects of pro-inflammatory cytokines on keratinocyte terminal differentiation.

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