**1. Introduction**

Wound healing is a complex process involving inflammation, cell proliferation, matrix deposition, and tissue remodeling [1,2]. During the inflammatory phase, infiltrating neutrophils and macrophages play an important role in the defense against bacterial infections and debridement of necrotic tissue [2]. In the proliferation phase, fibroblasts and myofibroblasts interact and produce extracellular matrix (mainly collagen), resulting in granulation tissue formation. The tissue remodeling process is associated with tissue maturation and collagen degradation by matrix metalloproteinases (MMPs), which are mainly derived from leukocytes and dermal fibroblasts [3]. Previously, several MMPs including MMP-2, -8, -9 and -13 have been reported to be involved in wound healing [4–7].

Neutrophils are the first infiltrating cells to appear within 24 h after wound creation and are necessary for host defense responses [8,9]. However, prolonged neutrophil infiltration is involved in the degradation of collagen by the production of proteinases such as MMPs. In-vitro collagen synthesis by fibroblasts is induced by transforming growth factor-β (TGF-β) [10,11] and inhibited by interferon (IFN)-γ [12,13].

IFN-γ is mainly secreted by CD4+ helper T cells, NK cells, and NKT cells and contributes to the activation of immune cells [14]. IFN-γ is also associated with both neutrophil recruitment and cell clearance through apoptosis [15]. Indeed, in the thrombus resolution process, which resembles wound healing, the absence of IFN-γ accelerates thrombus resolution by enhancing MMP-9 but not MMP-2 [16]. As for IFN-γ's role in wound healing, in a mouse acute open wound model [14] and a post-scald burn injury model [17], IFN-γKO mice exhibited accelerated healing and enhanced TGF-β expression compared with WT mice, suggesting that IFN-γ makes a negative contribution to the skin wound healing process. While treatment with TNFα plus IFN-γ-stimulated monocytes/macrophages in diabetic rat wounds improved the delay in wound healing [18], IFN-γ's role in wound healing remains controversial.

With this background, we focused on the e ffects of IFN-γ deficiency on the proliferation phase of skin wound healing using a mouse model with full-thickness wounds. Here, we show that IFN-γ is required for the repair of skin wounds in the proliferation phase due to its regulation of neutrophilic inflammatory responses, including the activation of MMP-2 (Gelatinase A) which is mainly derived from neutrophils.
