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.
Highlights
Wound healing is a complex process involving inflammation, cell proliferation, matrix deposition, and tissue remodeling [1,2]
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]
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]
Summary
Wound healing is a complex process involving inflammation, cell proliferation, matrix deposition, and tissue remodeling [1,2]. While treatment with TNF-α 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 effects of IFN-γ deficiency on the proliferation phase of skin wound healing using a mouse model with full-thickness wounds. 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
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