Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds

PLoS One. 2017 Jan 20;12(1):e0170500. doi: 10.1371/journal.pone.0170500. eCollection 2017.


Diabetic non-healing wounds are a major clinical problem. The mechanisms leading to poor wound healing in diabetes are multifactorial but unresolved inflammation may be a major contributing factor. The complement system (CS) is the most potent inflammatory cascade in humans and contributes to poor wound healing in animal models. Signal transducer and activator of transcription 4 (STAT4) is a transcription factor expressed in immune and adipose cells and contributes to upregulation of some inflammatory chemokines and cytokines. Persistent CS and STAT4 expression in diabetic wounds may thus contribute to chronic inflammation and delayed healing. The purpose of this study was to characterize CS and STAT4 in early diabetic wounds using db/db mice as a diabetic skin wound model. The CS was found to be activated early in the diabetic wounds as demonstrated by increased anaphylatoxin C5a in wound fluid and C3-fragment deposition by immunostaining. These changes were associated with a 76% increase in nucleated cells in the wounds of db/db mice vs.

Controls: The novel classical CS inhibitor, Peptide Inhibitor of Complement C1 (PIC1) reduced inflammation when added directly or saturated in an acellular skin scaffold, as reflected by reduced CS components and leukocyte infiltration. A significant increase in expression of STAT4 and the downstream macrophage chemokine CCL2 and its receptor CCR2 were also found in the early wounds of db/db mice compared to non-diabetic controls. These studies provide evidence for two new promising targets to reduce unresolved inflammation and to improve healing of diabetic skin wounds.

MeSH terms

  • Animals
  • Complement Activation / physiology*
  • Complement C5a / physiology
  • Diabetes Complications / physiopathology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Inflammation / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction
  • STAT4 Transcription Factor / physiology*
  • Signal Transduction / physiology
  • Wound Healing / physiology
  • Wounds and Injuries / complications
  • Wounds and Injuries / physiopathology*


  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Complement C5a