Knockdown of sodium channel Nax reduces dermatitis symptoms in rabbit skin

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Abstract

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Nax is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Nax using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Nax knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Nax knockdown. In addition, expression of COX-2, IL-1β, IL-8, and S100A9, which are downstream genes of Nax and are involved in dermatitis pathogenesis, were also decreased by Nax knockdown. Our data show that knockdown of Nax relieved dermatitis symptoms in vivo and indicate that Nax is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.

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Fig. 1: Knockdown of Nax expression relieved dermatitic symptoms induced by HDM extract and OXZ in rabbit skin.
Fig. 2: Epidermal hyperplasia, dermal inflammatory infiltrate, and aberrant differentiation of the epidermis were reduced in dermatitic skin by Nax knockdown.
Fig. 3: Infiltration of inflammatory cells was decreased in dermatitic skin by Nax knockdown.
Fig. 4: Upregulation of TSLP, PAR-2, and proinflammatory genes was reduced in dermatitic skin by Nax knockdown.

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Acknowledgements

We thank Dr Philippe Tessier (Université Laval, Quebec City, QC, Canada) for the S100A9 antibody. This study was supported by internal funding from the Division of Plastic and Reconstructive Surgery, Northwestern University, Feinberg School of Medicine. We thank Dr David Dolivo for the critical review of the manuscript.

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Correspondence to Thomas A. Mustoe or Seok Jong Hong.

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Zhao, J., Jia, S., Xie, P. et al. Knockdown of sodium channel Nax reduces dermatitis symptoms in rabbit skin. Lab Invest (2020). https://doi.org/10.1038/s41374-020-0371-1

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