Targeting miR‐223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds

Abstract

Argonaute 2 bound mature microRNA (Ago2‐miRNA) complexes are key regulators of the wound inflammatory response and function in the translational processing of target mRNAs. In this study, we identified four wound inflammation‐related Ago2‐miRNAs (miR‐139‐5p, miR‐142‐3p, miR‐142‐5p, and miR‐223) and show that miR‐223 is critical for infection control. miR‐223 Y/− mice exhibited delayed sterile healing with prolonged neutrophil activation and interleukin‐6 expression, and markedly improved repair of Staphylococcus aureus‐infected wounds. We also showed that the expression of miR‐223 was regulated by CCAAT/enhancer binding protein alpha in human neutrophils after exposure to S. aureus peptides. Treatment with miR‐223 Y/−‐derived neutrophils, or miR‐223 antisense oligodeoxynucleotides in S. aureus‐infected wild‐type wounds markedly improved the healing of these otherwise chronic, slow healing wounds. This study reveals how miR‐223 regulates the bactericidal capacity of neutrophils at wound sites and indicates that targeting miR‐223 might be of therapeutic benefit for infected wounds in the clinic.

Mechanistic Actions of microRNAs in Diabetic Wound Healing

“…Based on the available data, miR-223 is involved in the subtle control of different pathological conditions, ranging from inflammation [ 186 , 187 , 188 ] to infection [ 189 ] and cancer [ 190 ]. Neutrophils are an essential part of the innate immune response as they are critical for the first line of defense against bacteria and fungi.…”

“…Neutrophils are an essential part of the innate immune response as they are critical for the first line of defense against bacteria and fungi. De Kerckhove and colleagues showed that miR-223 is expressed in neutrophils, controlled by the transcription factor c/EBPα and it represses IL6 production, therefore restraining neutrophil activation and allowing S. aureus growth in wounds [ 189 ]. Consequently, knock-down of miR-223 using anti-sense oligonucleotides improves wound-healing [ 189 ].…”

Identification of Specific miRNAs in Neutrophils of Type 2 Diabetic Mice: Overexpression of miRNA-129-2-3p Accelerates Diabetic Wound Healing

“…*P , 0.05, **P , 0.01, ***P , 0.001. migration, and invasion in gastric cancer (27). We further elucidated the function of miR-223 in skin wound healing by analyzing miR-223 knockout mice (28). Similarly, miR-31 was highly expressed during the transition from the inflammatory to the proliferative phase in an in vivo human skin wound healing model, and the overexpression of miR-31 promoted cell proliferation and migration in human primary keratinocytes (29).…”

Micro RNA therapy for infected wounds

“…While it is today well accepted that miRNAs can function as critical regulators of tissue repair (Luan et al , ), the specific miRNAs involved and the wound healing phases during which they primarily function remain unclear in many cases. In this issue of EMBO Molecular Medicine , de Kerckhove et al () describe a novel approach to identify functional miRNAs that are elevated in response to skin injury and identify miRNA‐223 (miR‐223) as a potential therapeutic target able to influence acute inflammation in S. aureus‐ infected wounds (Fig ).…”

“…Targeting specific miRNAs represents a promising strategy as a means of fighting different pathologies. In their study, de Kerckhove et al () investigate the therapeutic potential of targeting miR‐223 during wound healing using mice with a specific deletion of miR‐223 (miR‐223 Y/− ). Live imaging revealed increased recruitment of neutrophils in miR‐223 Y/− mice as early as 12 h post‐injury.…”