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

Maiko de Kerckhove; Katsuya Tanaka; Takahiro Umehara; Momoko Okamoto; Sotaro Kanematsu; Hiroko Hayashi; Hiroki Yano; Soushi Nishiura; Shiho Tooyama; Yutaka Matsubayashi; Toshimitsu Komatsu; Seongjoon Park; Yuka Okada; Rina Takahashi; Yayoi Kawano; Takehisa Hanawa; Keisuke Iwasaki; Tadashige Nozaki; Hidetaka Torigoe; Kazuya Ikematsu; Yutaka Suzuki; Katsumi Tanaka; Paul Martin; Isao Shimokawa; Ryoichi Mori

doi:10.15252/emmm.201809024

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

Maiko de Kerckhove, Katsuya Tanaka, Takahiro Umehara, Momoko Okamoto, Sotaro Kanematsu, Hiroko Hayashi, Hiroki Yano, Soushi Nishiura, Shiho Tooyama, Yutaka Matsubayashi, Toshimitsu Komatsu, Seongjoon Park, Yuka Okada, Rina Takahashi, Yayoi Kawano, Takehisa Hanawa, Keisuke Iwasaki, Tadashige Nozaki, Hidetaka Torigoe, Kazuya IkematsuYutaka Suzuki, Katsumi Tanaka, Paul Martin, Isao Shimokawa, Ryoichi Mori^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

12 Citations (Scopus)

168 Downloads (Pure)

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.

Original language	English
Article number	e9024
Number of pages	21
Journal	EMBO Molecular Medicine
Volume	10
Issue number	10
Early online date	31 Aug 2018
DOIs	https://doi.org/10.15252/emmm.201809024
Publication status	Published - 1 Oct 2018

Keywords

inflammation
miR-223
neutrophil
skin wound healing
Staphylococcus aureus

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10.15252/emmm.201809024

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de Kerckhove, M., Tanaka, K., Umehara, T., Okamoto, M., Kanematsu, S., Hayashi, H., Yano, H., Nishiura, S., Tooyama, S., Matsubayashi, Y., Komatsu, T., Park, S., Okada, Y., Takahashi, R., Kawano, Y., Hanawa, T., Iwasaki, K., Nozaki, T., Torigoe, H., ... Mori, R. (2018). Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds. EMBO Molecular Medicine, 10(10), [e9024]. https://doi.org/10.15252/emmm.201809024

de Kerckhove, Maiko ; Tanaka, Katsuya ; Umehara, Takahiro ; Okamoto, Momoko ; Kanematsu, Sotaro ; Hayashi, Hiroko ; Yano, Hiroki ; Nishiura, Soushi ; Tooyama, Shiho ; Matsubayashi, Yutaka ; Komatsu, Toshimitsu ; Park, Seongjoon ; Okada, Yuka ; Takahashi, Rina ; Kawano, Yayoi ; Hanawa, Takehisa ; Iwasaki, Keisuke ; Nozaki, Tadashige ; Torigoe, Hidetaka ; Ikematsu, Kazuya ; Suzuki, Yutaka ; Tanaka, Katsumi ; Martin, Paul ; Shimokawa, Isao ; Mori, Ryoichi. / Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds. In: EMBO Molecular Medicine. 2018 ; Vol. 10, No. 10.

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title = "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-223Y/− 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-223Y/−-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.",

keywords = "inflammation, miR-223, neutrophil, skin wound healing, Staphylococcus aureus",

author = "{de Kerckhove}, Maiko and Katsuya Tanaka and Takahiro Umehara and Momoko Okamoto and Sotaro Kanematsu and Hiroko Hayashi and Hiroki Yano and Soushi Nishiura and Shiho Tooyama and Yutaka Matsubayashi and Toshimitsu Komatsu and Seongjoon Park and Yuka Okada and Rina Takahashi and Yayoi Kawano and Takehisa Hanawa and Keisuke Iwasaki and Tadashige Nozaki and Hidetaka Torigoe and Kazuya Ikematsu and Yutaka Suzuki and Katsumi Tanaka and Paul Martin and Isao Shimokawa and Ryoichi Mori",

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de Kerckhove, M, Tanaka, K, Umehara, T, Okamoto, M, Kanematsu, S, Hayashi, H, Yano, H, Nishiura, S, Tooyama, S, Matsubayashi, Y, Komatsu, T, Park, S, Okada, Y, Takahashi, R, Kawano, Y, Hanawa, T, Iwasaki, K, Nozaki, T, Torigoe, H, Ikematsu, K, Suzuki, Y, Tanaka, K, Martin, P, Shimokawa, I & Mori, R 2018, 'Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds', EMBO Molecular Medicine, vol. 10, no. 10, e9024. https://doi.org/10.15252/emmm.201809024

Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds. / de Kerckhove, Maiko; Tanaka, Katsuya; Umehara, Takahiro; Okamoto, Momoko; Kanematsu, Sotaro; Hayashi, Hiroko; Yano, Hiroki; Nishiura, Soushi; Tooyama, Shiho; Matsubayashi, Yutaka; Komatsu, Toshimitsu; Park, Seongjoon; Okada, Yuka; Takahashi, Rina; Kawano, Yayoi; Hanawa, Takehisa; Iwasaki, Keisuke; Nozaki, Tadashige; Torigoe, Hidetaka; Ikematsu, Kazuya; Suzuki, Yutaka; Tanaka, Katsumi; Martin, Paul; Shimokawa, Isao; Mori, Ryoichi.

In: EMBO Molecular Medicine, Vol. 10, No. 10, e9024, 01.10.2018.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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AU - de Kerckhove, Maiko

AU - Tanaka, Katsuya

AU - Umehara, Takahiro

AU - Okamoto, Momoko

AU - Kanematsu, Sotaro

AU - Hayashi, Hiroko

AU - Yano, Hiroki

AU - Nishiura, Soushi

AU - Tooyama, Shiho

AU - Matsubayashi, Yutaka

AU - Komatsu, Toshimitsu

AU - Park, Seongjoon

AU - Okada, Yuka

AU - Takahashi, Rina

AU - Kawano, Yayoi

AU - Hanawa, Takehisa

AU - Iwasaki, Keisuke

AU - Nozaki, Tadashige

AU - Torigoe, Hidetaka

AU - Ikematsu, Kazuya

AU - Suzuki, Yutaka

AU - Tanaka, Katsumi

AU - Martin, Paul

AU - Shimokawa, Isao

AU - Mori, Ryoichi

PY - 2018/10/1

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N2 - 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-223Y/− 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-223Y/−-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.

AB - 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-223Y/− 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-223Y/−-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.

KW - inflammation

KW - miR-223

KW - neutrophil

KW - skin wound healing

KW - Staphylococcus aureus

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