Staphylococcus aureus Triggers Induction of miR-15B-5P to Diminish DNA Repair and Deregulate Inflammatory Response in Diabetic Foot Ulcers

Horacio A. Ramirez, Irena Pastar, Ivan Jozic, Olivera Stojadinovic, Rivka C. Stone, Nkemcho Ojeh, Joel Gil Rodriguez, Stephen C Davis, Robert Kirsner, Marjana Tomic-Canic

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes in which bacterial presence, including the frequent colonizer Staphylococcus aureus, contributes to inhibition of healing. MicroRNAs (miRs) play a role in healing and host response to bacterial pathogens. However, the mechanisms by which miR response to cutaneous S. aureus contributes to DFU pathophysiology are unknown. Here, we show that S. aureus inhibits wound closure and induces miR-15b-5p in acute human and porcine wound models and in chronic DFUs. Transcriptome analyses of DFU tissue showed induction of miR-15b-5p to be critical, regulating many cellular processes, including DNA repair and inflammatory response, by suppressing downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT. Using a human wound model, we confirmed that S. aureus-triggered miR-15b-5p induction results in suppression of the inflammatory- and DNA repair-related genes IKBKB and WEE1. Inhibition of DNA repair and accumulation of DNA breaks was functionally confirmed by the presence of the pH2AX within colonized DFUs. We conclude that S. aureus induces miR-15b-5p, subsequently repressing DNA repair and inflammatory response, showing a mechanism of inhibition of healing in DFUs previously unreported, to our knowledge. This underscores a previously unknown role of DNA damage repair in the pathophysiology of DFUs colonized with S. aureus.

Original languageEnglish (US)
Pages (from-to)1187-1196
Number of pages10
JournalJournal of Investigative Dermatology
Volume138
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Diabetic Foot
DNA Repair
Staphylococcus aureus
Repair
DNA
I-kappa B Kinase
Wounds and Injuries
Fibroblast Growth Factor 2
Pathogens
Medical problems
DNA Breaks
MicroRNAs
Gene Expression Profiling
Diabetes Complications
DNA Damage
Genes
Tissue
Swine
Skin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Staphylococcus aureus Triggers Induction of miR-15B-5P to Diminish DNA Repair and Deregulate Inflammatory Response in Diabetic Foot Ulcers. / Ramirez, Horacio A.; Pastar, Irena; Jozic, Ivan; Stojadinovic, Olivera; Stone, Rivka C.; Ojeh, Nkemcho; Gil Rodriguez, Joel; Davis, Stephen C; Kirsner, Robert; Tomic-Canic, Marjana.

In: Journal of Investigative Dermatology, Vol. 138, No. 5, 01.05.2018, p. 1187-1196.

Research output: Contribution to journalArticle

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abstract = "Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes in which bacterial presence, including the frequent colonizer Staphylococcus aureus, contributes to inhibition of healing. MicroRNAs (miRs) play a role in healing and host response to bacterial pathogens. However, the mechanisms by which miR response to cutaneous S. aureus contributes to DFU pathophysiology are unknown. Here, we show that S. aureus inhibits wound closure and induces miR-15b-5p in acute human and porcine wound models and in chronic DFUs. Transcriptome analyses of DFU tissue showed induction of miR-15b-5p to be critical, regulating many cellular processes, including DNA repair and inflammatory response, by suppressing downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT. Using a human wound model, we confirmed that S. aureus-triggered miR-15b-5p induction results in suppression of the inflammatory- and DNA repair-related genes IKBKB and WEE1. Inhibition of DNA repair and accumulation of DNA breaks was functionally confirmed by the presence of the pH2AX within colonized DFUs. We conclude that S. aureus induces miR-15b-5p, subsequently repressing DNA repair and inflammatory response, showing a mechanism of inhibition of healing in DFUs previously unreported, to our knowledge. This underscores a previously unknown role of DNA damage repair in the pathophysiology of DFUs colonized with S. aureus.",
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