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

**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**


Received: 27 September 2019; Accepted: 10 November 2019; Published: 12 November 2019

**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 sugges<sup>t</sup> 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
