LEKTI domain 6 displays anti-inflammatory action in vitro and in a
murine atopic dermatitis model
Background: Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a
serine protease inhibitor consisting of multiple domains. A loss of
function mutation is described in Netherton patients that show severe
symptoms of atopic lesions and itch. Objectives: LEKTI domain 6 (LD6)
has shown strong serine protease-inhibitory action in in vitro
assays and thus it was tested in vitro and in vivo for
potential anti-inflammatory action in models of atopic skin disease.
Methods: Human skin equivalents were treated with LD6 and an
inflammatory reaction was challenged by kallikrein-related endopeptidase
5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells
stimulated with KLK5, SLIGRL and histamine by calcium imaging. The
effect of topically administered LD6 (0.4–0.8 %) in lipoderm was
compared to a topical formulation of betamethasone-diproprionate (0.5
%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga
mice sensitized to house dust mite antigen. Endpoints were clinical
scoring of the mice as well as determination of scratching behaviour.
Results: KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin
equivalents. This upregulation was reduced by pre-incubation with LD6.
KLK5 as well as histamine induced calcium influx in a population of
neurons. LD6 significantly reduced the calcium response to both stimuli.
When administered onto lesional skin of NC/Nga mice, both LD6 and
betamethasone-dipropionate significantly reduced the inflammatory
reaction. The effect on itch behaviour was less pronounced. Conclusions:
Topical administration of LD6 might be new therapeutic option for
treatment of lesional atopic skin.