Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis

doi:10.1016/j.jaci.2014.06.014

Journal of Allergy and Clinical Immunology

Volume 134, Issue 4, October 2014, Pages 792-799

https://doi.org/10.1016/j.jaci.2014.06.014 Get rights and content

The epidermis protects human subjects from exogenous stressors and helps to maintain internal fluid and electrolyte homeostasis. Filaggrin is a crucial epidermal protein that is important for the formation of the corneocyte, as well as the generation of its intracellular metabolites, which contribute to stratum corneum hydration and pH. The levels of filaggrin and its degradation products are influenced not only by the filaggrin genotype but also by inflammation and exogenous stressors. Pertinently, filaggrin deficiency is observed in patients with atopic dermatitis regardless of filaggrin mutation status, suggesting that the absence of filaggrin is a key factor in the pathogenesis of this skin condition. In this article we review the various causes of low filaggrin levels, centralizing the functional and morphologic role of a deficiency in filaggrin, its metabolites, or both in the etiopathogenesis of atopic dermatitis.

Section snippets

Filaggrin in normal epidermis

Although still present in keratohyalin granules of the stratum granulosum, 400-kDa profilaggrin polymers are released, proteolytically cleaved, and then dephosphorylated into 10 to 12 identical filaggrin monomers by enzymes, such as furin, endoproteinase 1, calpain 1, matriptase, and elastase 2.1, 22, 23, 24, 25 The liberated filaggrin monomers aggregate keratin filaments into tight bundles, resulting in collapse and flattening of corneocytes.²⁶ Additional cytosolic proteins, such as keratins

Genetic causes of reduced filaggrin levels

Loss-of-function mutations in 1 or both alleles of FLG result in reduced or completely absent levels of epidermal filaggrin, respectively (Table I)2, 3, 11, 12, 13, 14, 15, 16, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 Approximately 10% of Northern European subjects from the general population are heterozygous mutation carriers, and approximately 0.1% are homozygous.⁴ The prevalence of FLG mutations in Chinese, Japanese, and Korean subjects reaches 3% to 6%.⁴

Environmental causes of reduced filaggrin levels

There is sparse information available about environmental conditions and exogenous stressors that can reduce epidermal filaggrin levels (Table I). However, monomeric filaggrin is hydrolyzed in a humidity-sensitive fashion as environmental humidity decreases and after a rapid shift from a humid to a dry environment.¹⁴ The higher prevalence of AD in American children residing in areas with low relative humidity, low mean temperature, and more days of central heating could be explained by the

Inflammation-driven reductions in filaggrin levels

T_H2 skin inflammation, as observed in patients with AD, downregulates filaggrin, NMF, and caspase-14 levels in lesional and nonlesional skin, apparently independent of FLG mutation status.11, 12, 39, 40, 41, 42, 43, 44 In contrast, the T_H1-related cytokine IFN-γ appears to significantly augment filaggrin expression, potentially balancing T_H2 skewing in patients with AD.¹² Although the role of the innate immune system on filaggrin expression has not yet been thoroughly investigated, activation

Filaggrin deficiency affects epidermal protein expression and organization

Inherited and acquired filaggrin deficiency modifies both the intracellular and extracellular architecture of keratinocytes, as well as the normal physiology of the epidermis. At the light-microscopy level, the SC is thicker than normal, and the granular cell layer is either completely absent or strongly reduced in patients with IV or AD.⁴ At the ultrastructural level, the cytoskeleton of granular cells shows perinuclear retraction, and the distribution of both corneodesmosomes and TJs appears

Filaggrin deficiency interferes with lipid secretion

Because of the cytoskeletal abnormalities described above, cargo loading into lamellar bodies is also impaired, and secretion is partially compromised in patients with IV and AD, resulting in entombment of some lamellar bodies within corneocytes.⁶⁷ Although impaired secretion appears to reduce the normal quantities and organization of the extracellular lamellar bilayers,⁶⁹ there also appear to be further abnormalities in free fatty acid and ceramide chain length in patients with AD independent

Filaggrin deficiency increases skin pH, activating serine proteases that compromise barrier function

The skin of FLG mutation carriers shows reduced hydration and increased transepidermal water loss caused by reduced levels of filaggrin metabolites, including NMFs, which regulate not only SC hydration but also the pH of the SC.76, 77 The reduction in NMF increases the normally acidic SC pH with an allele dose-dependent effect whereby homozygous FLG mutation carriers have the highest pH levels.⁶⁷ Yet a compensatory upregulation of the sodium-hydrogen antiporter seems to counteract this pH

Protease activation stimulates pruritus and T_H2 inflammation in patients with AD

In addition to the direct destructive effects of kallikreins, they also bind to the protease-activated receptor type 2,⁸⁰ which not only downregulates lamellar body secretion but also initiates a cascade of innate inflammatory responses, including activation of thymic stromal lymphopoietin (TSLP) protein from keratinocytes,⁸³ the master switch that initiates T_H2 inflammatory responses.83, 84 TSLP is highly expressed in keratinocytes from lesional skin of patients with AD, and its secretion can

Filaggrin deficiency permits increased allergen penetration and enhances immune reactivity

Recently generated filaggrin-null mice serve as models for IV without AD.⁹⁶ Here double-allele mutations in pro-FLG are responsible for the inherited dysfunctional skin barrier.⁷⁵ Notably, when kept under nonsterile conditions, these mice show accelerated allergen penetration through the SC, as well as an enhanced contact hypersensitivity response.⁹⁶ However, the flaky tail mouse model also had spontaneous inflammation under normal conditions and serves as a model for early AD with filaggrin

Filaggrin deficiency predisposes to microbial colonization and invasion

Filaggrin, likely because of its role in SC acidification, seems to protect against colonization with certain microorganisms. Accordingly, acidification of growth medium with exogenous UCA or pyrrolidone-5-carboxylic acid reduced growth rates and final cell densities of Staphylococcus aureus.¹⁰⁷ Moreover, S aureus α-toxin preferentially targets and destroys filaggrin-deficient keratinocytes, whereas normal filaggrin expression increases sphingomyelinase secretion, thereby reducing the number of

Placing filaggrin deficiency in the center of AD pathogenesis

We surmise that AD only develops in those filaggrin-deficient subjects who are exposed to environmental triggers, such as low humidity, high-pH surfactants, pets, pollen, microorganisms, and psychological stress and who can mount an immunologic response to these triggers at the same time. Although it is clear that inherited filaggrin deficiency is not a prerequisite for the development of AD, we believe that acquired reductions of filaggrin and its degradation products in such FLG wild-type

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: Supported by the COST Action TD1206 StanDerm. J.P.T. is a Lundbeck Foundation Fellow and is supported by an unrestricted grant.

: Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Reviews and feature articleCauses of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis

Section snippets

Filaggrin in normal epidermis

Genetic causes of reduced filaggrin levels

Environmental causes of reduced filaggrin levels

Inflammation-driven reductions in filaggrin levels

Filaggrin deficiency affects epidermal protein expression and organization

Filaggrin deficiency interferes with lipid secretion

Filaggrin deficiency increases skin pH, activating serine proteases that compromise barrier function

Protease activation stimulates pruritus and TH2 inflammation in patients with AD

Filaggrin deficiency permits increased allergen penetration and enhances immune reactivity

Filaggrin deficiency predisposes to microbial colonization and invasion

Placing filaggrin deficiency in the center of AD pathogenesis

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

J Allergy Clin Immunol

J Invest Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

Dev Biol

J Dermatol Sci

J Invest Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Biol Chem

J Biol Chem

J Invest Dermatol

Biochim Biophys Acta

J Invest Dermatol

J Invest Dermatol

Dev Biol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Hum Evol

J Invest Dermatol

J Allergy Clin Immunol

J Invest Dermatol

Exp Cell Res

Am J Pathol

Am J Pathol

J Lipid Res

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

J Invest Dermatol

J Dermatol Sci

J Invest Dermatol

Am J Pathol

Allergol Int

J Allergy Clin Immunol

J Invest Dermatol

J Allergy Clin Immunol

Cell

Filaggrin—revisited

Int J Cosmet Sci

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Nat Genet

Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity

Allergy

Ichthyosis vulgaris: the filaggrin mutation disease

Br J Dermatol

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Nat Genet

Skin barrier integrity and natural moisturising factor levels after cumulative dermal exposure to alkaline agents in atopic dermatitis

Acta Derm Venereol

Tight junction defects in patients with atopic dermatitis

J Allergy Clin Immunol

Reviews and feature article
Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis

Protease activation stimulates pruritus and T_H2 inflammation in patients with AD