Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation

Kanno, Emi; Tanno, Hiromasa; Masaki, Airi; Sasaki, Ayako; Sato, Noriko; Goto, Maiko; Shisai, Mayu; Yamaguchi, Kenji; Takagi, Naoyuki; Shoji, Miki; Kitai, Yuki; Sato, Ko; Kasamatsu, Jun; Ishii, Keiko; Miyasaka, Tomomitsu; Kawakami, Kaori; Imai, Yoshimichi; Iwakura, Yoichiro; Maruyama, Ryoko; Tachi, Masahiro; Kawakami, Kazuyoshi

doi:10.3390/ijms20225657

Open AccessArticle

Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation

by

Emi Kanno

^1,*

,

Hiromasa Tanno

¹,

Airi Masaki

²,

Ayako Sasaki

²,

Noriko Sato

²,

Maiko Goto

¹,

Mayu Shisai

¹,

Kenji Yamaguchi

²,

Naoyuki Takagi

²,

Miki Shoji

²,

Yuki Kitai

³,

Ko Sato

⁴,

Jun Kasamatsu

⁴,

Keiko Ishii

³,

Tomomitsu Miyasaka

⁵,

Kaori Kawakami

⁵,

Yoshimichi Imai

²

,

Yoichiro Iwakura

⁶,

Ryoko Maruyama

¹,

Masahiro Tachi

² and

Kazuyoshi Kawakami

^3,4 Show full author list Hide full author list

¹

Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 9808575, Japan

²

Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 9808575, Japan

³

Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 9808575, Japan

⁴

Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 9808575, Japan

⁵

Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 9818558, Japan

⁶

Division of Laboratory Animals, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 2788510, Japan

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2019, 20(22), 5657; https://doi.org/10.3390/ijms20225657

Submission received: 27 September 2019 / Revised: 8 November 2019 / Accepted: 10 November 2019 / Published: 12 November 2019

(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)

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Abstract

Interferon (IFN)-γ is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-γ is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in wound healing in vivo. In the present study, we analyzed how the defect of IFN-γ affects wound healing. Full-thickness wounds were created on the backs of wild type (WT) C57BL/6 and IFN-γ-deficient (KO) mice. We analyzed the percent wound closure, wound breaking strength, accumulation of leukocytes, and expression levels of COL1A1, COL3A1, and matrix metalloproteinases (MMPs). IFN-γKO mice exhibited significant attenuation in wound closure on Day 10 and wound breaking strength on Day 14 after wound creation, characteristics that are associated with prolonged neutrophil accumulation. Expression levels of COL1A1 and COL3A1 mRNA were lower in IFN-γKO than in WT mice, whereas expression levels of MMP-2 (gelatinase) mRNA were significantly greater in IFN-γKO than in WT mice. Moreover, under neutropenic conditions created with anti-Gr-1 monoclonal antibodies, wound closure in IFN-γKO mice was recovered through low MMP-2 expression levels. These results suggest that IFN-γ may be involved in the proliferation and maturation stages of wound healing through the regulation of neutrophilic inflammatory responses.

Keywords: interferon-γ; wound healing; neutrophils; matrix metalloproteinase-2

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MDPI and ACS Style

Kanno, E.; Tanno, H.; Masaki, A.; Sasaki, A.; Sato, N.; Goto, M.; Shisai, M.; Yamaguchi, K.; Takagi, N.; Shoji, M.; et al. Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation. Int. J. Mol. Sci. 2019, 20, 5657. https://doi.org/10.3390/ijms20225657

AMA Style

Kanno E, Tanno H, Masaki A, Sasaki A, Sato N, Goto M, Shisai M, Yamaguchi K, Takagi N, Shoji M, et al. Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation. International Journal of Molecular Sciences. 2019; 20(22):5657. https://doi.org/10.3390/ijms20225657

Chicago/Turabian Style

Kanno, Emi, Hiromasa Tanno, Airi Masaki, Ayako Sasaki, Noriko Sato, Maiko Goto, Mayu Shisai, Kenji Yamaguchi, Naoyuki Takagi, Miki Shoji, and et al. 2019. "Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation" International Journal of Molecular Sciences 20, no. 22: 5657. https://doi.org/10.3390/ijms20225657

APA Style

Kanno, E., Tanno, H., Masaki, A., Sasaki, A., Sato, N., Goto, M., Shisai, M., Yamaguchi, K., Takagi, N., Shoji, M., Kitai, Y., Sato, K., Kasamatsu, J., Ishii, K., Miyasaka, T., Kawakami, K., Imai, Y., Iwakura, Y., Maruyama, R., ... Kawakami, K. (2019). Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation. International Journal of Molecular Sciences, 20(22), 5657. https://doi.org/10.3390/ijms20225657

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Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation

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