Inhibition of miR-139-5p by topical JTXK gel promotes healing of Staphylococcus aureus-infected skin wounds.

Abstract

BACKGROUND:

The inflammatory skin wound response is regulated by argonaute 2-bound microRNAs (Ago2-miRNAs) such as miR-139-5p, which inhibit transcription of their target mRNAs. Jiang Tang Xiao Ke (JTXK) is a traditional Chinese medicine that reduces miR-139-5p expression, suggesting that topical application of JTXK may have effects on wound healing.

METHODS:

miR-139-/- mice and wild-type (WT) mice were employed to characterize the in vivo effects of miR-139-5p on sterile wound healing. Neutrophil migration and activation into the wound site were examined by live imaging analysis in lys-EGFP mice and myeloperoxidase/aminophenyl fluorescein assays, respectively. In silico and in vitro studies in differentiated HL60 cells were performed to identify miR-139-5p's downstream mediator(s). miR-139-/- neutrophil transplantation (with or without Eif4g2-knockdown rescue) or a topical JTXK gel preparation (with or without miR-139-5p mimic rescue) were employed to characterize the in vivo effects of miR-139-5p and JTXK, respectively, on Staphylococcus aureus (S. aureus)-infected wound healing.

RESULTS:

miR-139-/- mice display impaired sterile wound healing but improved S. aureus-infected wound healing. Eif4g2, a protein that supports neutrophil proliferation and differentiation, was identified as a key downstream mediator of miR-139-5p. miR-139-/- mice show elevated neutrophilic activation and Eif4g2 upregulation. miR-139-/- neutrophils enhanced S. aureus-infected wound healing in an Eif4g2-dependent manner. Moreover, topical JTXK gel therapy also enhanced S. aureus-infected wound healing in a miR-139-5p-dependent manner.

CONCLUSIONS:

miR-139-5p negatively regulates the neutrophilic response during S. aureus-infected wound healing, suggesting that JTXK or other miR-139-5p suppressants may be effective for treating infected skin wounds.

• Authors: Weitao Zhang, Xu Qu, Zhang Zhu, Liwen Wang, Qian Qi, Pengjun Zhou, Xiaoli Wang, Wenna Li
• Journal: Cells & development (Cells Dev) Vol. 166 Pg. 203658 (06 2021) ISSN: 2667-2901 [Electronic] Netherlands
• PMID: 33994349 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Drugs, Chinese Herbal
• Eif4g2 protein, mouse
• Eukaryotic Initiation Factor-4G
• Gels
• MIRN139 microRNA, mouse
• MicroRNAs
• jiang tang xiao ke

Topics

• Administration, Topical
• Animals
• Drugs, Chinese Herbal (administration & dosage, pharmacology)
• Eukaryotic Initiation Factor-4G (metabolism)
• Gels (administration & dosage, pharmacology)
• Gene Knockdown Techniques
• Humans
• Inflammation (pathology)
• Mice
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Neutrophils (drug effects, metabolism)
• Skin (microbiology, pathology)
• Staphylococcal Infections (genetics, microbiology, pathology)
• Staphylococcus aureus (drug effects, physiology)
• Up-Regulation (drug effects, genetics)
• Wound Healing (drug effects, genetics)
• Wound Infection (genetics, microbiology)