ABSTRACT
Harlequin ichthyosis (HI) is a severe skin disease which leads to neonatal death in â¼50% of cases. It is the result of mutations in ABCA12, a protein that transports lipids required to establish the protective skin barrier needed after birth. To better understand the life-threatening newborn HI phenotype, we analysed the developing epidermis for consequences of lipid dysregulation in mouse models. We observed a pro-inflammatory signature which was characterized by chemokine upregulation in embryonic skin which is distinct from that seen in other types of ichthyosis. Inflammation also persisted in grafted HI skin. To examine the contribution of inflammation to disease development, we overexpressed interleukin-37b to globally suppress fetal inflammation, observing considerable improvements in keratinocyte differentiation. These studies highlight inflammation as an unexpected contributor to HI disease development in utero, and suggest that inhibiting inflammation may reduce disease severity.
Subject(s)
Ichthyosis, Lamellar/embryology , Ichthyosis, Lamellar/immunology , Animals , Cell Differentiation , Chemokines/genetics , Chemokines/immunology , Disease Models, Animal , Epidermis/embryology , Epidermis/immunology , Female , Humans , Ichthyosis, Lamellar/genetics , Ichthyosis, Lamellar/physiopathology , Interleukin-1/genetics , Interleukin-1/immunology , Keratinocytes/cytology , Male , Mice , Mice, Knockout , Phenotype , Skin/embryology , Skin/immunologyABSTRACT
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.