Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity

J Invest Dermatol. 2017 Nov;137(11):2380-2388. doi: 10.1016/j.jid.2017.06.003.

Hanna Niehues ¹, Lam C Tsoi ², Danique A van der Krieken ¹, Patrick A M Jansen ¹, Merel A W Oortveld ¹, Diana Rodijk-Olthuis ¹, Ivonne M J J van Vlijmen ¹, Wiljan J A J Hendriks ³, Richard W Helder ⁴, Joke A Bouwstra ⁴, Ellen H van den Bogaard ¹, Philip E Stuart ⁵, Rajan P Nair ⁵, James T Elder ⁶, Patrick L J M Zeeuwen ¹, Joost Schalkwijk ⁷

Affiliations

1 Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
2 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
3 Department of Cell Biology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
4 Leiden Academic Center for Drug Research, Department of Drug Delivery Technology, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.
5 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
6 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
7 Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. Electronic address: Joost.Schalkwijk@radboudumc.nl.

PMID: 28634035 DOI: 10.1016/j.jid.2017.06.003

Abstract

Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of Bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk.

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