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Roles of Activated Microglia in Hypoxia Induced Neuroinflammation in the Developing Brain and the Retina

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Abstract

Amoeboid microglial cells (AMCs) in the developing brain display surface receptors and antigens shared by the monocyte-derived tissue macrophages. Activation of AMCs in the perinatal brain has been associated with periventricular white matter damage in hypoxic-ischemic conditions. The periventricular white matter, where the AMCs preponderate, is selectively vulnerable to hypoxia as manifested by death of premyelinating oligodendrocytes and degeneration of axons leading to neonatal mortality and long-term neurodevelopmental deficits. AMCs respond vigorously to hypoxia by producing excess amounts of inflammatory cytokines e.g. the tumor necrosis factor–α (TNF-α) and interleukin-1β (IL-1β) along with glutamate, nitric oxide (NO) and reactive oxygen species which collectively cause oligodendrocyte death, axonal degeneration as well as disruption of the immature blood brain barrier. A similar phenomenon is observed in the hypoxic developing cerebellum in which activated AMCs induced Purkinje neuronal death through production of TNF-α and IL-1β via their respective receptors. Hypoxia is also implicated in retinopathy of prematurity in which activation of AMCs has been shown to cause retinal ganglion cell death through production of TNF-α and IL-1β and NO. Because AMCs play a pivotal role in hypoxic injuries in the developing brain affecting both neurons and oligodendrocytes, a fuller understanding of the underlying molecular mechanisms of microglial activation under such conditions would be desirable for designing of a novel therapeutic strategy for management of hypoxic damage.

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Abbreviations

AMCs:

Amoeboid microglial cells

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

CNS:

Central nervous system

CR3:

Complement type 3 receptors

CSF-1:

Colony stimulating factor

GluR2-4:

AMPA glutamate receptors

IGF-1:

Insulin-like growth factor-1

IGF-2:

Insulin-like growth factor-2

IL-1 β:

Interleukin-1β

IL-1R:

Interleukin 1 receptor

iNOS:

Nitric oxide synthase

MBP:

Myelin basic protein

MCP-1:

Monocyte chemoattractant protein-1

M-CSF:

Macrophage-colony stimulating factor

MHC I:

Major histocompatibility class I antigens

MHC II:

Major histocompatibility class II antigens

NMDA:

N-methyl-D-aspartate

NR1, NR2A-D:

NMDA receptor subunits

NO:

Nitric oxide

PWM:

Periventricular white matter

PWMD:

Periventricular white matter damage

RGC:

Retinal ganglion cell

RGCs:

Retinal ganglion cells

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

TβRI and TβRII:

Transforming growth factor receptors I and II

TGF-βl:

Transforming growth factor βl

TNF-α:

Tumor necrosis factor –α

TNF-R1, TNF-R2 :

TNF receptor 1 or 2

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Acknowledgements

This study was supported by a research grant (R181-000-120-213) from National Medical Research Council of Singapore. We thank Dr. Viswanathan Sivakumar for providing the technical assistance. There is no conflict of interest among the authors.

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  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, MD10, Singapore, 117597, Singapore

    Charanjit Kaur, Gurugirijha Rathnasamy & Eng-Ang Ling

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  1. Charanjit Kaur
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  2. Gurugirijha Rathnasamy
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  3. Eng-Ang Ling
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Correspondence to Charanjit Kaur or Eng-Ang Ling.

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Charanjit Kaur and Eng-Ang Ling contributed equally to this manuscript.

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Kaur, C., Rathnasamy, G. & Ling, EA. Roles of Activated Microglia in Hypoxia Induced Neuroinflammation in the Developing Brain and the Retina. J Neuroimmune Pharmacol 8, 66–78 (2013). https://doi.org/10.1007/s11481-012-9347-2

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