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Staphylococcus aureus impairs cutaneous wound healing by activating the expression of a gap junction protein, connexin-43 in keratinocytes

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Abstract

Chronic wounds have been considered as major medical problems that may result in expensive healthcare. One of the common causes of chronic wounds is bacterial contamination that leads to persistent inflammation and unbalanced host cell immune responses. Among the bacterial strains that have been identified from chronic wounds, Staphylococcus aureus is the most common strain. We previously observed that S. aureus impaired mouse cutaneous wound healing by delaying re-epithelialization. Here, we investigated the mechanism of delayed re-epithelialization caused by S. aureus infection. With the presence of S. aureus exudate, the migration of in vitro cultured human keratinocytes was significantly inhibited and connexin-43 (Cx43) was upregulated. Inhibition of keratinocyte migration by S. aureus exudate disappeared in keratinocytes where the expression of Cx43 knocked down. Protein kinase phosphorylation array showed that phosphorylation of Akt-S473 was upregulated by S. aureus exudate. In vivo study of Cx43 in S. aureus-infected murine splinted cutaneous wound model showed upregulation of Cx43 in the migrating epithelial edge by S. aureus infection. Treatment with a PI3K/Akt inhibitor reduced Cx43 expression and overcame the wound closure impairment by S. aureus infection in the mouse model. This may contribute to the development of treatment to bacterium-infected wounds.

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Funding

Internal funding from the Division of Plastic and Reconstructive Surgery.

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Authors and Affiliations

  1. Department of Life Sciences, College of Science and Engineering, Texas A&M University-Corpus Christi, Corpus Christi, TX, 78412, USA

    Wei Xu

  2. Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Elodi Dielubanza, Amanda Maisel, Thomas Mustoe, Seok Hong & Robert Galiano

  3. Division of Combat Wound Repair, US Army Institute of Surgical Research, JB Fort Sam Houston, San Antonio, TX, 78234, USA

    Kai Leung

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  1. Wei Xu
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  2. Elodi Dielubanza
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  4. Kai Leung
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Xu, W., Dielubanza, E., Maisel, A. et al. Staphylococcus aureus impairs cutaneous wound healing by activating the expression of a gap junction protein, connexin-43 in keratinocytes. Cell. Mol. Life Sci. 78, 935–947 (2021). https://doi.org/10.1007/s00018-020-03545-4

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