title: Suppressed recruitment of alternatively activated macrophages reduces TGF-β1 and impairs wound healing in streptozotocin-induced diabetic mice.
abstract: BACKGROUND
  Diabetes mellitus inhibits wound-induced angiogenesis, impairing the wound healing process and leading to the development of chronic wounds. Impaired healing of diabetic wounds is caused by persistent pro-inflammatory macrophages recruited to the granulation tissue; however, little is known about the phenotype of the macrophages involved in diabetic wound healing. The present study was conducted to examine the involvement of macrophages in impaired wound healing using streptozotocin (STZ)-induced diabetic mice.
  
  
  METHODS
  Full-thickness skin wounds were created on the backs of mice treated with STZ or vehicle.
  
  
  RESULTS
  Compared with controls, wound healing and angiogenesis were suppressed in STZ-treated mice, with attenuated expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 in wound granulation tissue. STZ-treated mice exhibited enhanced recruitment of classically activated macrophages (M1) expressing inducible nitric oxide synthase (iNOS) and suppressed recruitment of alternatively activated macrophages (M2) expressing transforming growth factor-beta-1 (TGF-β1). Treatment of diabetic mice with TGF-β1 restored wound healing and angiogenesis and normalized M1/M2 macrophage polarization in the granulation tissue.
  
  
  CONCLUSIONS
  These results suggest that an imbalance of macrophage phenotypes contributes to impaired wound healing in STZ-induced diabetic mice, and treatment with cytokines derived from M2 macrophages may be an effective therapeutic strategy to increase angiogenesis and promote healing of diabetic wounds.
authors: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Departments of Endocrinology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Shin-ichiro
authors: S
authors: Okizaki
authors: Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Yoshiya
authors: Y
authors: Ito
authors: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Kanako
authors: K
authors: Hosono
authors: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Departments of Endocrinology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Kazuhito
authors: K
authors: Oba
authors: Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Hirotoki
authors: H
authors: Ohkubo
authors: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Hideki
authors: H
authors: Amano
authors: Departments of Endocrinology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
authors: Masayoshi
authors: M
authors: Shichiri
authors: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan. Electronic address: mmajima@med.kitasato-u.ac.jp.
authors: Masataka
authors: M
authors: Majima
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D053773:Transforming Growth Factor beta1; D013311:Streptozocin
keywords: Diabetes; Macrophages; Phenotype; Wound healing