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

Peng Yang, Anatol Manaenko, Feng Xu, Liyan Miao, Gaiqing Wang, Xuezhen Hu, Zhen Ni Guo, Qin Hu, Richard E. Hartman, William J. Pearce, Andre Obenaus, John H. Zhang, Gang Chen, Jiping Tang

Research output: Contribution to journalArticlepeer-review

Abstract

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 30 g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6 h 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.

Original languageEnglish
Pages (from-to)157-164
Number of pages8
JournalExperimental Neurology
Volume283
Issue numberPt A
DOIs
StatePublished - Sep 1 2016

ASJC Scopus Subject Areas

  • Neurology
  • Developmental Neuroscience

Keywords

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

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