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

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, Spink5Klk5 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 Spink5Camp succumbed perinatally due to skin barrier defect, similarly to Spink5. Joint invalidation of Klk5 and Camp significantly extended survival of Spink5Klk5Camp 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.