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



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.



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.



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.
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.
Peng
P
Yang
Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Departments of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: anatolmanaenko@gmail.com.
Anatol
A
Manaenko
Department of Emergency Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: sz_xf@suda.edu.cn.
Feng
F
Xu
Departments of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: miaolysuzhou@163.com.
Liyan
L
Miao
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.
Gaiqing
G
Wang
Department of Emergency Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: 649321276@qq.com.
Xuezhen
X
Hu
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.
Zhen-Ni
ZN
Guo
Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: huqinle@gmail.com.
Qin
Q
Hu
Departments of Psychology, Loma Linda University, Loma Linda, CA, USA. Electronic address: behavioralneuroscience@gmail.com.
Richard E
RE
Hartman
Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: wpearce@llu.edu.
William J
WJ
Pearce
Departments of Pediatrics, Loma Linda University, Loma Linda, CA, USA. Electronic address: aobenaus@llu.edu.
Andre
A
Obenaus
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.
John H
JH
Zhang
Departments of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: nju_neurosurgery@163.com.
Gang
G
Chen
Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: jtang@llu.edu.
Jiping
J
Tang
D015119:Aminocaproic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000150:complications*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005106:Exploratory Behavior / Q000187:drug effects; D005341:Fibrinolysin / Q000008:administration & dosage / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*
D005343:Fibrinolytic Agents; D009419:Nerve Tissue Proteins; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D005341:Fibrinolysin; D015119:Aminocaproic Acid
ICH; Neuroinflammation; PDGF-D; PDGFR-β