Loss of filaggrin (FLG) causes Ichthyosis vulgaris. Reduced filaggrin expression compromises epidermal barrier function and is associated with atopic dermatitis, allergy and asthma. The flaky tail mouse harbors two mutations that affect the skin barrier, Flg, resulting in hypomorphic FLG expression, and Tmem79 inactivating transmembrane protein 79. Mice defective only for Tmem79 featured dermatitis and systemic atopy, but also Flg BALB/c congenic mice developed eczema, high IgE and spontaneous asthma, suggesting that Flg protects from atopy. In contrast, a targeted Flg knock out mutation backcrossed to BALB/c did not result in dermatits or atopy. To resolve this discrepancy, we generated Flg-deficient mice on pure BALB/c background by inactivating Flg in BALB/c embryos. These animals feature an ichthyosis phenotype, barrier defect and facilitated percutaneous sensitization. However, they do not develop dermatitis or atopy. Whole genome sequencing of the atopic Flg BALB/c congenics revealed that they were homozygous for the atopy-causing Tmem79 mutation. In summary, we show that Flg-deficiency does not cause atopy in mice, in line with lack of atopic disease in a fraction of Ichthyosis vulgaris patients carrying two FLG null alleles. However, absence of FLG likely promotes and modulates dermatitis caused by other genetic barrier defects.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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