Filaggrin deficient mice have a lower threshold for cutaneous allergen sensitization but do not develop spontaneous skin inflammation or atopy

Abstract

Defects of filaggrin (FLG) compromise epidermal barrier function and represent an important known genetic risk factor for atopic dermatitis (AD), but also for systemic atopy, including allergic sensitization and asthma. The flaky tail mouse model, widely used to address mechanisms of atopy induction by barrier-defective skin, harbors two mutations that affect the skin barrier, the mutation Flgft, resulting in near-complete loss of FLG expression, and the matted mutation inactivating transmembrane protein 79 (Tmem79). Upon separation of the two mutant loci, which are closely linked on chromosome 3, mice defective only for Tmem79 featured pronounced dermatitis and systemic atopy. Upon extensive backcross to BALB/c, also Flgft/ft mice (assumed to be wild type for Tmem79), developed AD-like dermatitis and reproduced the human ‘atopic march’, with high IgE levels and spontaneous asthma, suggesting a key role for functional Flg in protection from atopy also in mice. In contrast, BALB/c mice congenic for a targeted Flg knock out mutation did not develop skin inflammation or atopy. To resolve this discrepancy, we generated Flg-deficient mice on a pure BALB/c background by inactivating the Flg gene in BALB/c embryos. These animals feature an ichthyosis phenotype, but do not develop spontaneous dermatitis or systemic atopy. We sequenced the genome of the atopic Flgft BALB/c congenics and discovered that they were unexpectedly homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that Flg-deficiency does not cause atopy in mice. This finding is in line with lack of atopic disease in a fraction of Ichthyosis vulgaris patients carrying two FLG null alleles. However, absence of FLG may promote and modulate dermatitis caused by other genetic barrier defects, as skin inflammation in Tmem79ma/maFlgft/ft BALB/c congenics is qualitatively different compared to Tmem79ma/ma mice.

Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease

“…On the other hand, skin barrier disruption due to genetic defects in barrier molecules such as filaggrin mutations can initiate AD. 177 , 178 , 179 The same question is also valid for asthma and CRS. 177 In atopic skin, there has been a reduction in commensal bacteria and in patients with AD, a higher colonization index and increased pathogen density show a positive correlation with the skin lesions’ severity and the severity of the disease.…”

“…In other words, it is still unclear whether dysbiosis of the skin microbiome is one of the pathogenetic factors of AD or the cause of the onset of AD. On the other hand, skin barrier disruption due to genetic defects in barrier molecules such as filaggrin mutations can initiate AD 177‐179 . The same question is also valid for asthma and CRS 177 .…”

“…Reduced risk with perinatal and/or early-life microbial/allergen exposure [161,162] Reduced with endotoxin exposure in childhood [164] Higher abundance of certain gut bacteria was shown in asthmatic subjects [165,166] Allergic rhinitis Alteration in normal nasal mucosal bacterial abundance and diversity was shown [169,170] Reduced risk with early-life exposure to environmental microbiota [155,171] Atopic dermatitis Altered abundance and diversity of skin microbiota compared to healthy skin [131,175,176,180] Early-life skin colonization of certain bacteria in AD [182] Increased risk with dysregulated gut-skin axis [176,183,184] Filaggrin mutation can initiate AD [177][178][179] Food allergy Increased risk with dysbiosis in gut environment [189,191] Increased risk with lower gut microbiota diversity at early infancy [190] Reduced risk maternal Mediterranean diet during lactation and gestation [193] Reduced risk with diet consisting of high levels of fruits and vegetables during infancy [194] Increased risk with high-sugar, high-fat, low short-chain fatty acid diets [195] sensitization. 155 Host microbiota has been primarily linked to asthma pathogenesis via gut microbial metabolites.…”