Abstract
Timely and sufficient M1 recruitment and M2 polarization are necessary for fibrosis during wound healing. The mechanism of how M2 mediates wound healing is worth exploring. Abnormally up-regulated connective tissue growth factor (CTGF) influences multiple organ fibrosis, including cardiac, pulmonary, hepatic, renal, and cutaneous fibrosis. Previous studies reported that M2 contributed to hepatic and renal fibrosis by secreting CTGF. It is worth discussing if M2 regulates fibrosis through secreting CTGF in wound healing. We established the murine wound model and inhibited macrophages during proliferation phase with clodronate liposomes in vivo. Macrophages depletion led to down-regulation of wound healing rates, collagen deposition, as well as expression of collagen 1/3 and Ki67. M2 was induced by interleukin-4 (IL-4) and measured by flow cytometry in vitro. Secreted pro-fibrotic and anti-fibrotic factors were tested by enzyme-linked immunosorbent assay (ELISA). M2 was polarized, which producing more CTGF, transforming growth factor-beta1 (TGF-β1), and IL-6, as well as less tumor necrosis factor-α (TNF-α) and IL-10. M2 CTGF gene was blocked using siCTGF. Effects of M2 on fibroblasts activities were detected by cell counting kit 8 (CCK8) and cellular wound healing assay. Expressions of related signaling pathway were assessed by western blotting. Blockade of CTGF in M2 deactivated fibroblasts proliferation and migration by regulating AKT, ERK1/2, and STAT3 pathway. Recombinant CTGF restored these effects. Our research, for the first time, indicated that M2 promoted wound healing by secreting CTGF, which further mediating proliferation and migration of fibroblasts via AKT, ERK1/2, and STAT3 pathway.
Highlights
Fibrous repair generally happens after organ injury[1]
3.1 Macrophages are associated with fibrosis during cutaneous wound healing
The wound healing delayed as a result of macrophage depletion (Fig. 2A)
Summary
Fibrous repair generally happens after organ injury[1]. In plastic surgery, fibrous repair is related to pathological scars and chronic refractory wounds, including hypertrophic scar (HTS), keloid (K), as well as diabetic ulcers. The first period, named fibre deposition, usually starts from the 4th or 5th day, remains active for about 1 week, and mitigates gradually. This period is paralleled with the inflammation phase and the tissue proliferation phase. Up-regulated connective tissue growth factor (CTGF) is closely related with multiple organ fibrosis, including cardiac, pulmonary, hepatic, renal, and cutaneous fibrosis. Previous studies have reported that M2-polarized macrophages contribute to hepatic and renal fibrosis by secreting CTGF. It is worth discussing if M2 macrophages regulate fibrosis through secreting CTGF in cutaneous wound healing
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