Filaggrin

Filaggrin (“filament-aggregating protein”) is made in the granular layer of the epidermis as a large precursor, profilaggrin, which is stored in keratohyalin granules. As skin cells mature into corneocytes, profilaggrin is dephosphorylated and cut into filaggrin monomers. These bind keratin filaments and collapse the cell into the flat, tough units of the stratum corneum. Filaggrin is later broken down (partly by caspase-14) into Natural Moisturising Factor (NMF), which includes free amino acids, urocanic acid and pyrrolidone carboxylic acid. NMF holds water in the skin and keeps its surface acidic. Filaggrin therefore matters for the physical strength of the skin barrier, for keeping foreign antigens out, and for limiting Transepidermal Water Loss (Agrawal & Woodfolk 2014).

Filaggrin [part-of] skin barrier Filaggrin [precedes] Natural Moisturising Factor Filaggrin [prevents] Transepidermal Water Loss

Genetics. Filaggrin deficiency was first tied to Ichthyosis Vulgaris, a dry, scaly-skin disorder. Reduced filaggrin was reported in eczema skin in 1996, and loss-of-function (null) mutations in the FLG gene on chromosome 1q21 were identified about a decade later. At least 49 truncating mutations are known. The commonest European mutations, R501X and 2282del4, made up 80% of FLG mutations in an Irish eczema cohort, compared with under 2% in a Singapore cohort. Asian populations carry different mutations (Agrawal & Woodfolk 2014). Carriers tend to have eczema that starts earlier and lasts longer, along with more atopy and asthma. They have about 3.3 times the risk of eczema (Lee et al. 2024). Still, most people with eczema have no FLG mutation, and some carriers never develop it.

Conflict: [Elias & Wakefield, Clin Rev Allergy Immunol, 2011] says up to 60% of Europeans with AD carry FLG mutations. [Furue, Int J Mol Sci, 2020] says rates range from 10% to 50% depending on ethnicity. Unresolved — add to open_questions.

Filaggrin [causes] Skin Barrier Dysfunction Filaggrin [causes] Ichthyosis Vulgaris Filaggrin [relates] Atopic March

Acquired filaggrin deficiency. Filaggrin can also be lost without any mutation. The Th2 Immune Response cytokines IL-4 and IL-13 suppress FLG expression through STAT6/STAT3 signalling, and IL-17A, IL-22, IL-25 and IL-31 lower it too (Furue 2020; Agrawal & Woodfolk 2014). Inflamed skin is therefore filaggrin-poor regardless of genes, which helps explain why barrier repair and anti-inflammatory treatment work together. In trials, Dupilumab, which blocks IL-4 and IL-13 signalling, restored FLG and loricrin expression (Furue 2020). Aryl hydrocarbon receptor activators such as coal tar and tapinarof increase filaggrin (Furue 2020). Low humidity reduces the breakdown of filaggrin into NMF (Elias & Wakefield 2011).

Th2 Immune Response [worsens] Filaggrin Dupilumab [supports] Filaggrin

Downstream effects: pH, proteases and microbes. Less filaggrin means less NMF and a higher stratum corneum pH. A higher pH activates serine proteases (kallikreins). These break down the junctions that hold skin cells together, block lipid secretion and release pre-formed IL-1 from corneocytes, which starts inflammation (Elias & Wakefield 2011). FLG mutations are also linked to changes in the skin bacteria, including more Staphylococcus aureus on lesional skin and in the nose. Filaggrin breakdown products appear to restrain S. aureus growth (Edslev et al. 2020). How central filaggrin is, though, is debated. In a human skin model, knocking filaggrin down did not alter stratum corneum permeability or lipids. AD patients with and without FLG mutations also showed similar skin penetration and Th2 responses when sensitised through healthy skin (Agrawal & Woodfolk 2014). Both findings argue against filaggrin loss alone being enough.

Conflict: [Elias & Wakefield, 2011] treats filaggrin deficiency (via raised pH and proteases) as a primary initiator of AD. [Agrawal & Woodfolk, 2014] cites ex vivo and human sensitisation data showing filaggrin loss alone does not change barrier permeability or Th2 sensitisation. Unresolved — add to open_questions.

Filaggrin [prevents] Staphylococcus aureus Filaggrin [relates] Skin Microbiome

Relevance for toddlers. Genetic testing for FLG is not part of routine care. The practical takeaway for parents is that a child with a strong family history of atopy, or very dry skin from early infancy, may have an inherently weaker barrier that needs consistent Emollient Therapy and gentle cleansing, such as Soap Substitutes rather than alkaline soap. A barrier-focused cream cannot fix a gene. However, barrier-repair products with ceramide-dominant lipid ratios at an acidic pH are designed around the biochemical defects that filaggrin loss causes (Elias & Wakefield 2011).

Emollient Therapy [treats] Skin Barrier Dysfunction Soap Substitutes [prevents] Skin Barrier Dysfunction

Connections

• Skin Barrier Dysfunction — FLG loss is the main genetic cause, source: Agrawal & Woodfolk 2014
• skin barrier — structural component of the stratum corneum, source: Agrawal & Woodfolk 2014
• Natural Moisturising Factor — filaggrin breakdown product, source: Agrawal & Woodfolk 2014
• Transepidermal Water Loss — filaggrin limits water loss, source: Agrawal & Woodfolk 2014
• Th2 Immune Response — IL-4/IL-13 suppress filaggrin, source: Furue 2020
• Dupilumab — restores FLG expression, source: Furue 2020
• Staphylococcus aureus — FLG mutations raise colonisation risk, source: Edslev 2020
• Skin Microbiome — FLG status shifts bacterial communities, source: Edslev 2020
• Ichthyosis Vulgaris — FLG-deficiency disorder often co-occurring with AD, source: Elias & Wakefield 2011
• Atopic March — FLG mutations linked to asthma risk, source: Agrawal & Woodfolk 2014
• Atopic Dermatitis — FLG mutations ~3.3x risk, source: Lee 2024
• Emollient Therapy — compensates for barrier defect, source: Elias & Wakefield 2011
• Soap Substitutes — avoid alkaline pH stress on a filaggrin-poor barrier, source: Elias & Wakefield 2011
• Atopic Dermatitis — genetic barrier cause, source: Medicina 2024; DermNet
• Skin pH — filaggrin-derived acids keep SC acidic, source: Elias & Wakefield 2011
• Pets and Eczema — neonatal cat exposure raises eczema risk in FLG carriers, source: Bisgaard 2008 via Ownby & Johnson 2011
• Eczema Prognosis — FLG null mutations OR 4.31 for early-onset-persistent AD, source: Paternoster 2018