Role of PDGF-D and PDGFR-β in neuroinflammation in experimental ICH mice model

Exp Neurol. 2016 Sep;283(Pt A):157-64. doi: 10.1016/j.expneurol.2016.06.010. Epub 2016 Jun 11.


Objective: Inflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-α), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-β (PDGFR-β) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-β compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice.

Methods: A blood injection model of ICH was used in eight-week old male CD1 mice (weight 30g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ε-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated.

Results: ICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-α production. Administration of recombinant PDGF-D induced TNF-α production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-β activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration.

Conclusion: ICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.

Keywords: ICH; Neuroinflammation; PDGF-D; PDGFR-β.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminocaproic Acid / administration & dosage
  • Aminocaproic Acid / pharmacology
  • Animals
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism
  • Brain Edema / drug therapy
  • Brain Edema / etiology
  • Cerebral Hemorrhage / complications*
  • Disease Models, Animal
  • Encephalitis / drug therapy
  • Encephalitis / etiology*
  • Encephalitis / metabolism*
  • Encephalitis / pathology
  • Exploratory Behavior / drug effects
  • Fibrinolysin / administration & dosage
  • Fibrinolysin / pharmacology
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Imatinib Mesylate / administration & dosage
  • Imatinib Mesylate / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • Nerve Tissue Proteins / metabolism
  • Platelet-Derived Growth Factor / metabolism*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*


  • Fibrinolytic Agents
  • Nerve Tissue Proteins
  • Platelet-Derived Growth Factor
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta
  • Fibrinolysin
  • Aminocaproic Acid