Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury

Akhmetzyanova, Elvira R.; Kletenkov, Konstantin; Mukhamedshina, Yana; Rizvanov, Albert A.

doi:10.3389/fnsys.2019.00037

Cited by 76 publications

(75 citation statements)

References 159 publications

(173 reference statements)

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“…The switch from homeostatic microglia to activated, potentially pro-inflammatory, microglia has become an important indicator of pathology in the CNS [1,2]. This switch is also known as M1/M2 polarization, where classically activated pro-inflammatory M1 microglia and alternatively activated M2 microglia lie on opposite ends of a continuum of functional states [3,4]. The pro-inflammatory M1 polarisation of resident microglia is often referred to as "neuroinflammation" to distinguish it from inflammatory tissue responses with recruitment of peripheral immunocytes.…”

Section: Introductionmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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Section: Introductionmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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“…Neuroinflammatory microglial changes are associated with various pathologies, including, but not limited to, spinal cord injury, neurodegenerative diseases, and early-life stress [46][47][48][49] . Alterations in the form and frequency of physical microglial-axonal contacts, however, have been described in the most detail in multiple sclerosis (MS) and traumatic brain injury (TBI), therefore this review focuses on these two disease states [45,[50][51][52] .…”

Section: Introductionmentioning

confidence: 99%

Microglial process convergence on axonal segments in health and disease

Benusa

Lafrenaye

2020

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Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by physically interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these microglial process interactions is not well understood. Microglial-axonal contacts are present early in development and persist through adulthood, implicating microglial interactions in the regulation of axonal integrity in both the developing and mature central nervous system. Moreover, changes in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state, there are increased associations with specific axonal segments. In MS, there is enhanced contact with the axon initial segment and node of Ranvier, while, in TBI, microglia alter interactions with axons at the site of injury, as well as at the axon initial segment. In this article, we review the interactions of microglial processes with axonal segments, analyzing their associations with various axonal domains and how these interactions may differ between MS and TBI. Furthermore, we discuss potential functional consequences and molecular mechanisms of these interactions and how these may differ among various types of microglial-axonal interactions.

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“…IL‐6, IL‐2, and IL‐4 were described in this article as modulatory cytokines because they may induce and terminate inflammatory responses depending on the context of inflammation (Hoyer, Dooms, Barron, & Abbas, ; Luzina et al, ; Rothaug, Becker‐Pauly, & Rose‐John, ). These three cytokines are able to modulate microglial function (Akhmetzyanova, Kletenkov, Mukhamedshina, & Rizvanov, ; Recasens, Shrivastava, Almolda, Gonzalez, & Castellano, ; Rossi et al, ) as well as astrocyte activation (Alves et al, ; Brodie, Goldreich, Haiman, & Kazimirsky, ; Klein et al, ). Diapedesis and activation of other immunocompetent cells like neutrophils and lymphocytes within the brain can also be regulated by these modulatory cytokines (Erta, Quintana, & Hidalgo, ; Gadani, Cronk, Norris, & Kipnis, ; Gao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Short and long TNF‐alpha exposure recapitulates canonical astrogliosis events in human‐induced pluripotent stem cells‐derived astrocytes

Trindade

Loiola

Gasparotto

et al. 2020

Glia

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Astrogliosis comprises a variety of changes in astrocytes that occur in a contextspecific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animals, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human-induced pluripotent stem cells (iPSC)-derived astrocytes which replicate temporally intertwined aspects of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, production of cytokines, changes in morphology and function of iPSC-derived astrocytes exposed to TNF-α. We observed NF-kB p65 subunit nuclear translocation and increased gene expression of IL-1β, IL-6, and TNF-α in the first hours following TNF-α stimulation.After 24 hr, conditioned media from iPSC-derived astrocytes exposed to TNF-α exhibited increased secretion of inflammation-related cytokines. After 5 days, TNFα-stimulated cells presented a typical phenotype of astrogliosis such as increased immunolabeling of Vimentin and GFAP and nuclei with elongated shape and shrinkage. Moreover,~50% decrease in aspartate uptake was observed during the time course of astrogliosis with no evident cell damage, suggesting astroglial dysfunction.Together, our results indicate that human iPSC-derived astrocytes reproduce canonical events associated with astrogliosis in a time dependent fashion. The approach described here may contribute to a better understanding of mechanisms governing

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Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury

Cited by 76 publications

References 159 publications

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Microglial process convergence on axonal segments in health and disease

Short and long TNF‐alpha exposure recapitulates canonical astrogliosis events in human‐induced pluripotent stem cells‐derived astrocytes

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