Microglial—Neuronal interactions

doi:10.1016/0891-0618(93)90047-8

Journal of Chemical Neuroanatomy

Volume 6, Issue 4, July–August 1993, Pages 261-266

https://doi.org/10.1016/0891-0618(93)90047-8 Get rights and content

Abstract

The question of whether activated microglial cells are potentially harmful or beneficial to injured central nervous system neurons is being addressed by examining in vivo and _vitro findings. While observations made in vivo suggest that microglial activation is triggered by injured neurons and may aid in regeneration, in vitro data show production of neurotoxic agents by cultured microglia. An effort is made to find a common denominator in these apparently conflicting findings by discussing microglial activation during motor neuron regeneration and during delayed neuronal death occurring as a consequence of global forebrain ischemia.

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Microglia, CNS myeloid cells which are the self-renewing tissue resident macrophages, are heterogenous and survey the CNS parenchyma at steady state via a network of tiny processes. At rest, microglia are termed ramified, and phenotypically characterized by a small cell body, with fine processes extending outwards (Hristovska and Pascual, 2015; Lier et al., 2021; Morioka et al., 1993; Streit, 1993; Streit, 2002; Streit and Graeber, 1993). During insult or injury, microglia become active phagocytes and exhibit an activated, macrophage-like ameboid phenotype (Gopinath et al., 2020b; Shaerzadeh et al., 2020; Streit, 2002).
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Triggering receptor expressed on myeloid cells 2 (TREM2) forms a receptor complex with DNAX-activating protein of 12 kDa (DAP12) on the microglial plasma membrane. A wide variety of protein and non-protein ligands, including lipids and DNA, can bind to TREM2, inducing the activation of microglia via DAP12. Both Trem2 and Dap12 have been identified as causative genes for Nasu-Hakola disease, which causes presenile dementia in association with bone cysts. Furthermore, TREM2/DAP12 signaling represents an essential inducer of the activated microglial phenotype in neuronal diseases, including Alzheimer's disease. Therefore, most previous studies examining TREM2/DAP12 have focused on their roles in microglia under pathological conditions. However, a growing body of evidence has demonstrated the involvement of TREM2/DAP12 signaling in the regulation of physiological functions in microglia. Accordingly, by examining the importance of TREM2/DAP12 in the regulation of microglial activity during development, homeostasis, and aging in the brain, this review elucidates the roles played by this complex in the healthy brain.
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Citation Excerpt :
Although synaptic pruning by microglia during development was only demonstrated in this decade, a similar role of microglial “synaptic stripping” has been known in the context of neural injury for half a century (Blinzinger and Kreutzberg, 1968). After motor nerve injury, activated microglia adhere to cell bodies of injured motor neurons and enwrap them (Streit, 1993; Moran and Graeber, 2004). During this process, microglial processes invade the clefts of axosomatic synapses and disconnect presynaptic input from the surface of the injured neurons (Kreutzberg, 1993; Schiefer et al., 1999), presumably reducing their excitotoxicity (Eroglu and Barres, 2010).
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We have previously demonstrated that CD4⁺ T cells transiently rescue facial motoneurons (FMN) from axotomy-induced death in immunodeficient mice. Three subpopulations of motoneurons have been observed within the facial motor nucleus following axotomy: one that always survives axotomy (50%), one that is amenable to rescue from axotomy-induced death through the addition of neurotrophic factors or CD4⁺ T cells (30–40%), and one that always dies after axotomy (10–15%). The objective of this study was to anatomically map the extent of axotomy-induced cell death and immune cell rescue in the facial nucleus to study the differential survival capabilities of each subpopulation. Wild-type (WT) mice, recombinase activating gene 2 knockout (RAG-2 KO) mice, and RAG-2 KO mice reconstituted with CD4⁺ T cells were subjected to right facial nerve axotomy. At 4 weeks post-axotomy, topographical mapping of axotomy-induced cell death throughout the rostro-caudal extent of the facial nucleus was accomplished in accordance with previously published maps of the subnuclear arrangement of the facial neurons. The results indicate that all 3 subpopulations of FMN can be found in each of the subnuclear groups throughout the entire rostro-caudal extent of the facial nucleus. These data are discussed in context of recent work in amyotrophic lateral sclerosis, a fatal motoneuron disease.
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Journal of Chemical Neuroanatomy

Abstract

References (29)

Production of superoxide by a CNS macrophage, the microglia

FEBS Lett.

Brain injury induces c-fos protein(s) in nerve and glial-like cells in adult mammalian brain

Brain Res.

Lipopolysaccharide-stimulated rat brain macrophages release NGF in vitro

Dev. Biol.

Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate

Neurosci. Lett.

Peripheral nerve lesion produces increased levels of MHC antigens in the CNS

J. Neuroimmunol.

Expression of Ia antigens on perivascular and microglial cells after sublethal and lethal neuronal injury

Exp. Neurol.

Basic FGF in astroglial, microglial, and neuronal cultures: characterization of binding sites and modulation of release by lymphokines and trophic factors

J. Neurosci.

Cytotoxicity of microglia

Glia

Displacement of synaptic terminals from regenerating motoneurons by microglial cells

Zeitschr. f. Zellforsch.

Neuronotrophic activity associated with monocyte growth factors and products of stimulated monocytes

Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease

Glia

Calcitonin gene-related peptide and peripheral nerve regeneration

Ann. NY Acad. Sci.

Antigen presentation and tumor cytotoxicity by interferon-γ-treated microglial cells

Eur. J. Immunol.

Immunocytochemical study of an early microglial activation in ischemia

J. Cereb. Blood Flow Metab.

Cited by (97)

The complex role of inflammation and gliotransmitters in Parkinson's disease

Non-pathological roles of microglial TREM2/DAP12: TREM2/DAP12 regulates the physiological functions of microglia from development to aging

Dual functions of microglia in the formation and refinement of neural circuits during development

Use of laser microdissection in the investigation of facial motoneuron and neuropil molecular phenotypes after peripheral axotomy

CD4<sup>+</sup> T cell-mediated facial motoneuron survival after injury: Distribution pattern of cell death and rescue throughout the extent of the facial motor nucleus

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes