108 Targeting the toll-like receptor pathway to treat scaling in the autosomal recessive congenital ichthyoses

Abstract

Autosomal recessive congenital ichthyosis (ARCI) represents a group of non-syndromic ichthyoses, which include a range of ichthyoses such as congenital ichthyosiform erythroderma, lamellar ichthyosis and harlequin ichthyosis, resulting from gene mutations in at least 9 different genes. They are characterized by a hyperkeratotic epidermis, resulting in varying severities of scaling and erythroderma. The current first-line treatment is with oral retinoids although the mechanism of action is not well understood. Although retinoids are effective in treating skin scaling they have a number of side effects that limits treatment to certain individuals. New treatments based on an understanding of the mechanisms of hyperkeratosis have the potential to treat the majority of ARCI individuals regardless of genotype. Hyperkeratotic skin displays elevated keratin 1 (K1) expression and interleukin 1-alpha (IL1a) signalling. We have previously identified the NFkB/IL1a pathway as being the key innate immune pathway that leads to hyperkeratosis. We show here that the upstream effector of hyperkeratosis is the innate immune receptor, toll-like receptor 1/2 (TLR1/2). Agonists of this receptor upregulate K1 and IL1a, and are sufficient to induce hyperkeratosis in organotypic culture models. Therefore, we sought to target this pathway using a novel small molecule inhibitor that targets TLR1/2, in our Arachidonate 12-lipoxygenase and Transglutaminase1 shRNA knockdown ARCI cell culture model and human ARCI patient cells. Here we show K1 and IL1a are upregulated in knockdown cells compared to scrambled controls and that treatment with a TLR1/2 inhibitor rapidly reduces K1 protein expression levels and IL1a signalling. This therefore indicates that the use of this inhibitor in ARCI individuals, as well as other skin diseases with a scaling hyperkeratotic phenotype, could provide a more targeted treatment for hyperkeratosis with a reduced side-effect profile compared to retinoids.