Cathelicidin represents a new target for manipulation of skin inflammation in Netherton syndrome

Abstract

Netherton syndrome (NS) is a severe ichthyosis caused by inactivating mutations in the SPINK5 gene encoding the serine protease inhibitor LEKTI. Spink5^-/- mice recapitulate NS and die perinatally from extensive dehydration as a result of a severe defect of the epidermal barrier. We showed that deletion of Klk5 in Spink5^-/- rescues neonatal lethality (Furio et al., 2015). However, Spink5^-/-Klk5^-/- mice developed skin shedding and inflammation during the first week from birth and the majority (70%) succumbed on P7. The remaining mice lived short (i.e. mean survival was 5 months) indicating alternative inflammatory pathways. Since cathelicidin is increased in Spink5^-/- epidermis, we investigated whether it could be implicated in NS pathology. Ablation of Camp in Spink5^-/- suppressed epidermal inflammation and restored abnormal epidermal differentiation, nevertheless, it failed to inhibit overdesquamation and Spink5^-/-Camp^-/- succumbed perinatally due to skin barrier defect, similarly to Spink5^-/-. Joint invalidation of Klk5 and Camp significantly extended survival of Spink5^-/-Klk5^-/-Camp^-/- mice. We provide evidence that cathelicidin is implicated in NS-associated skin inflammation in vivo. Therefore, marketed products that are known to reduce cathelicidin expression could be repurposed for the management of NS.

Keywords: Cathelicidin; Epidermal inflammation; KLK5; Klk5; Mouse models; Netherton syndrome; SPINK5.