Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis

Abstract

Summary Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.

Hair follicles modulate skin barrier function

“…Since HI is the most severe skin barrier disease, we reasoned that targeted deletion of Abca12, the causative gene mutated in HI 9,10 , would provide us a tool to disrupt lamellar granules and interrogate barrier function in different epithelial sub-compartments. We therefore first generated mice harboring a null allele of Abca12 that is constitutively disrupted by a LacZ insertion between exons 3 and 4, similar to previously described 33 (Figure S2A-B). Newborn homozygous mutant pups (Abca12-KO) recapitulated HI features, including taut, shiny skin; thickened and compacted stratum corneum; and death from rapid dehydration [34][35][36] (Figure 2A).…”