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Atopic dermatitis (AD) is an inflammatory skin disease characterised by pruritus, dry skin, crusting and lichenification with a worldwide lifetime prevalence ranging from 1.8% to 44% across different populations.1 This disease poses significant medical, psychosocial and financial burdens for children and their families.2 AD has a complex aetiology that includes an impaired skin barrier, excessive type 2 T-helper lymphocyte (Th2) activity, reduced skin antimicrobial proteins and skin colonisation with Staphylococcus aureus.3 Filaggrin is a major structural protein in the stratum corneum (SC) of the epidermis and plays a critical role in maintaining the skin barrier function. The discovery that null mutations in the filaggrin gene (FLG) are associated with AD represented a significant breakthrough in the understanding of this complex disorder and the key role of skin barrier dysfunction in AD.4 Filaggrin mutations have reliably shown to be associated with the development of AD and remain an important paradigm for thinking about the pathophysiology of AD and subsequent allergies. Here, we review the central role of decreased filaggrin levels in the pathogenesis of AD, describe how filaggrin deficiency causes so-called ‘leaky skin’ and discuss promising strategies for AD treatment and prevention.
Role of filaggrin
The epidermis, specifically the SC, is the first-line defence between humans and the environment, including allergens, irritants and microbes. The SC is also responsible for minimising water loss from the body. The SC is composed of corneocyte cells surrounded by cell envelopes (CE) embedded in an intercellular lamellae. Sometimes, this is referred to as the ‘bricks’ and ‘mortar’ model of the skin barrier, and while not a perfect analogy, it captures the basic ideas nicely. Corneocytes (the ‘bricks’) are flattened, anucleate keratinocytes linked by protein bridges called corneodesmosomes. The CE is a tough, insoluble protein structure that replaces the plasma membrane in corneocytes. The lamellae (the ‘mortar’) is composed of ceramides, cholesterol and free fatty acids. Both the CE and the lamellae contribute to the hydrophobic lipid barrier.5
Filaggrin is a key protein in the SC and is critical for maintenance of the epidermal barrier. FLG is located on chromosome 1q21 as part of the epidermal differentiation complex, a set of genes involved in epithelial differentiation. Filaggrin plays an important role in formation of the CE. It also is responsible for aggregating keratin filaments, which is essential for aligning and flattening the corneocytes as part of the differentiation process.6
Filaggrin is degraded into amino acids that make up a component of natural moisturising factor (NMF). NMF contributes to epidermal hydration and barrier function. Additionally, these same amino acids help maintain the acidic pH environment of epidermis, which is important for many functions including antimicrobial activity, synthesis of ceramides and modulation of enzymes required for epidermal differentiation.7
Thus, filaggrin is an important part of skin barrier function: it plays a direct structure role for mechanical strength, it breaks down into hygroscopic amino acids as part of NMF and it even helps modulate pH, affecting enzyme activity.
Filaggrin and atopic dermatitis
Studies involving thousands of patients have demonstrated FLG loss-of-function mutations play a critical role in the pathogenesis of AD. Two recent meta-analyses have estimated the OR of developing AD with FLG-null mutations is 4.788 and 3.12.9 Filaggrin is such a key protein in the development of AD that in certain Northern European populations, up to 49% of patients with AD have FLG mutations.10
On a cellular level, FLG mutations are associated with cytoskeletal abnormalities and lamellae disorganisation, causing an impaired epidermal barrier.11 FLG mutations reduce the skin’s natural hydration due to less NMF production. Fewer filaggrin amino acid breakdown products create an alkaline environment in the epidermis that decreases production of ceramide lipids12 and prematurely degrades corneodesmosomes, further damaging the barrier.11 The increased pH also facilitates colonisation with certain micro-organisms, specifically S. aureus. Filaggrin helps keep S. aureus growth at bay, and this is demonstrated by the fact that AD patients with FLG mutations have a sevenfold increase in the risk of bacterial infections compared with patients with AD and wild-type FLG.13
Decreased filaggrin production results in an impaired epidermal barrier, reduced natural skin hydration and increased skin colonisation with S. aureus, three key features of AD. It has been proposed that AD with FLG mutations may represent a distinct phenotype compared with patients with wild-type FLG that has an earlier onset and is more severe and persistent.14 Patients also demonstrate a higher incidence of eczema herpeticum (skin infections with herpesvirus) than patients with wild-type FLG,15 which could theoretically be due to the decreased antimicrobial activity associated with the alkaline environment in addition to the barrier dysfunction.
Remarkably, even in patients with AD and normal FLG genotypes, filaggrin levels are found to be low in the presence of AD-type inflammation. The epidermal cytokine environment is known to play a role in the pathogenesis of AD. Specifically, Th2 signalling in the epidermis increases AD susceptibility16 and keratinocytes differentiated in presence of Th2 cytokines (interleukin (IL)-4 and IL-13) demonstrate decreased filaggrin expression.17 Thus, we know that AD patients are functionally deficient in filaggrin regardless of their filaggrin genotype.
Bringing these ideas together, a recent paper examining proteomic changes downstream of filaggrin deficiency concludes that loss of FLG is itself an important primary pathogenic factor in the development of AD.18 The authors underscore that the mechanism of FLG reduction—be it via genotype, inflammatory cytokine effects, or some combination—may not be important, and that all can lead to the development of AD.
We are therefore presented with a ‘chicken-or-egg’ dilemma of whether the complex barrier dysfunction cascade observed in AD originates from filaggrin loss-of-function mutations or from the inflammatory cytokine environment. Conceptualising our current understanding of filaggrin expression in AD in this manner is useful as it allows us to appreciate that, regardless of the primary cause, a barrier dysfunction is observed in AD, and this leaky skin must be addressed.
Treatment and prevention strategies
Research bears out that treatment and prevention strategies geared towards decreasing leaky skin and maintaining the epidermal barrier are promising. Specifically, increased use of emollients results in improved control of AD and a decreased need for topical corticosteroids (TCS) by improving the skin barrier.19 Furthermore, we know that impairment of skin barrier at birth precedes clinical AD20 and moisturisation from birth to 6 months of life is a cost-effective, safe strategy for the prevention of AD.21 22 Anti-inflammatory agents, including TCS and topical pimecrolimus cream, used on inflamed AD sites for a short-term basis are known to normalise filaggrin levels, thus effectively reversing the functional deficiency.23
We now know that epithelial barrier dysfunction may lead to other problems, including development of the atopic march. Children with FLG mutations have a higher risk of developing allergies and asthma24 and are at increased risk for developing peanut allergies with early-life environmental peanut exposure, likely due to transcutaneous sensitisation through an impaired skin barrier.25 Thus, since we know that moisturisation is an effective strategy for improving the skin barrier and preventing AD, it is imperative that we capitalise on this cost-effective, low-risk approach. This is true now more than ever as some of the very treatments for AD can actually contribute to barrier damage. Specifically, prolonged TCS use has been shown to decrease components of NMF, damage the skin barrier structure and suppress filaggrin levels,23 highlighting the need to maximise therapies that improve barrier function and minimise longer term TCS exposure.
Prevention strategies for AD and the atopic march have potential to show profound benefits similar to those observed in the Learning Early about Peanut Allergy (LEAP) trial for allergy prevention. The authors of the LEAP trial found that infants at high risk for atopic disease who sustained peanut consumption in first year of life showed deceased peanut allergy at age 60 months. This study suggests that prevention of atopy in high-risk infants is possible through early and specific interventions and we believe AD prevention with moisturisation shows similar promise.26
Of interest, a recently approved medication for AD called dupilumab is a biological agent that blocks IL-4 and IL-13 signalling, important inflammatory cytokines in AD. The efficacy of this drug points towards a primary immune-driven disease.27 However, it is important to remember that these cytokines are also associated with decreased filaggrin expression, returning us to our ‘chicken-or-egg’ dilemma: the cause and effect cannot be clearly delineated at this time, so we must focus on our established understanding of the barrier dysfunction and resultant leaky skin.
Filaggrin has been shown to be a key protein in the pathogenesis of AD and demonstrates that barrier dysfunction is absolutely critical to our understanding AD. Treating and preventing barrier dysfunction with emollients seems more important than ever to improve AD outcomes and help decrease subsequent allergic sensitisation.
Contributors PAL created the outline for the manuscript and edited it for submission. MD created the initial draft.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.