Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats.
Hypoxic injury in the perinatal period results in periventricular white matter (PWM) lesions with axonal damage and oligodendroglial loss. It also alters macrophage function by perpetuating expression of inflammatory mediators. Relevant to this is the preponderance of amoeboid microglial cells (AMC) characterized as active macrophages in the developing PWM. This study aimed to determine if AMC produce proinflammatory cytokines that may be linked to the oligodendroglial loss observed in hypoxic PWM damage (PWMD). Wistar rats (1 day old) were subjected to hypoxia, following which upregulated expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), TNF receptor 1 (TNF-R(1)) and IL-1 receptor 1 (IL-1R(1)) was observed. This was coupled with apoptosis and expression of TNF-R(1) and IL-1R(1) in oligodendrocytes. Primary cultured microglial cells subjected to hypoxia (3% oxygen, 5% CO(2) and 92% nitrogen) showed enhanced expression of TNF-alpha and IL-1beta. Furthermore, mitogen-activated protein (MAP) kinase signaling pathway was involved in the expression of TNF-alpha and IL-1beta in microglia subjected to hypoxia. Our results suggest that following a hypoxic insult, microglial cells in the neonatal rats produce inflammatory cytokines such as TNF-alpha and IL-1beta via MAP kinase signaling pathway. These cytokines are detrimental to oligodendrocytes resulting in PWM lesion.
Deng
YiYu
Y
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lu
Jia
J
Sivakumar
Viswanathan
V
Ling
Eng Ang
EA
Kaur
Charanjit
C
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines