Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain.
Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC(+) OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC(+) oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.
Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Yiyu
Y
Deng
Graduate School, Southern Medical University, Guangzhou, PR China ; Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Di
D
Xie
Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Ming
M
Fang
Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Gaofeng
G
Zhu
Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Chunbo
C
Chen
Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
Hongke
H
Zeng
Defense Medical and Environmental Research Institute, DSO National Laboratories, Singapore.
Jia
J
Lu
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kaur
K
Charanjit
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha