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

doi:10.1016/j.expneurol.2016.06.010

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.

Authors

Peng Yang¹, Anatol Manaenko², Feng Xu³, Liyan Miao⁴, Gaiqing Wang⁵, Xuezhen Hu⁶, Zhen-Ni Guo⁷, Qin Hu⁸, Richard E Hartman⁹, William J Pearce¹⁰, Andre Obenaus¹¹, John H Zhang¹², Gang Chen¹³, Jiping Tang¹⁴

Affiliations

¹ Department of Emergency Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: yangpeng@suda.edu.cn.
² Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Departments of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: anatolmanaenko@gmail.com.
³ Department of Emergency Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: sz_xf@suda.edu.cn.
⁴ Departments of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: miaolysuzhou@163.com.
⁵ Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address: wanggq08@163.com.
⁶ Department of Emergency Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: 649321276@qq.com.
⁷ Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Neuroscience Center, Department of Neurology, The First Norman Bethune Hospital of Jilin University, Chang Chun, Jilin, China. Electronic address: zhen1ni2@163.com.
⁸ Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: huqinle@gmail.com.
⁹ Departments of Psychology, Loma Linda University, Loma Linda, CA, USA. Electronic address: behavioralneuroscience@gmail.com.
¹⁰ Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: wpearce@llu.edu.
¹¹ Departments of Pediatrics, Loma Linda University, Loma Linda, CA, USA. Electronic address: aobenaus@llu.edu.
¹² Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Departments of Anesthesiology, Loma Linda University, Loma Linda, CA, USA; Departments of Neurosurgery, Loma Linda University, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com.
¹³ Departments of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: nju_neurosurgery@163.com.
¹⁴ Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: jtang@llu.edu.

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 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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding