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, 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.