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\begin{document}

\title{LEKTI domain 6 displays anti-inflammatory action in vitro and in a
murine atopic dermatitis model}



\author[1]{Wolfgang Bäumer}%
\author[1]{Pascal Canbolat}%
\author[1]{Jenny Wilzopolski}%
\author[2]{Sabine Kaessmeyer}%
\author[3]{Marc Rüger}%
\author[3]{Hans-Jürgen Mägert}%
\author[4]{Wolf-Georg Forssmann}%
\affil[1]{Freie Universitat Berlin Fachbereich Veterinarmedizin}%
\affil[2]{Universitat Bern Vetsuisse Fakultat}%
\affil[3]{Hochschule Anhalt}%
\affil[4]{PHARIS Biotec GmbH}%


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  \date{May 17, 2024}


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\begin{abstract}
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 \emph{in vitro}
assays and thus it was tested \emph{in vitro} and \emph{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.%
\end{abstract}%



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