Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease

Delpech, Jean-Christophe; Herron, Shawn; Botros, Mina; Ikezu, Tsuneya

doi:10.1016/j.tins.2019.02.007

Cited by 144 publications

(134 citation statements)

References 90 publications

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“…Microglial derived FGF has been shown to be important for limiting astrocyte activation (Kang et al, 2014) although its specific effect on synaptic uptake by astrocytes has not yet been evaluated. In addition to the release of soluble factors, microglia have also been shown to communicate with other brain cell types through release of extracellular vesicles (Delpech, Herron, Botros, & Ikezu, ; Paolicelli, Bergamini, & Rajendran, ), which could also mediate microglial signaling to astrocytes in this context. Identifying the signals used by microglia to alter astrocyte synaptic uptake promises to provide a means to potently regulate astrocytic elimination of synapses which would be of great interest in pathological contexts in which aberrant glial function drives synaptic loss.…”

Section: Discussionmentioning

confidence: 99%

“…has not yet been evaluated. In addition to the release of soluble factors, microglia have also been shown to communicate with other brain cell types through release of extracellular vesicles (Delpech, Herron, Botros, & Ikezu, 2019;Paolicelli, Bergamini, & Rajendran, 2019), which could also mediate microglial signaling to astrocytes in this context.…”

Section: Microglia Instruct Synaptic Elimination By Astrocytesmentioning

confidence: 99%

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TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1‐month‐old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2‐dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Microglia Instruct Synaptic Elimination By Astrocytesmentioning

confidence: 99%

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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“…Astrocytes have a key role in neurotransmitter recycling, regulation of blood flow, energy metabolism, synaptogenesis, and synaptic transmission (183)(184)(185)(186)(187). Astrocytes signal physically through gap junctions (e.g., connexin Cx43), facilitating intercellular transmission (188,189).…”

Section: Spinal Cordmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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“…Interestingly, the composition of EVs strictly reflects the type and the activation state of donor cells, evoking, in the case of microglia, a detrimental or a beneficial response depending on the parental inflammatory or pro-resolving phenotype [ 65 , 66 ]. Due to these features, microglial EVs have been identified as mediators of inflammation and neurodegeneration, playing a pivotal role in spreading pathological misfolded protein aggregates [ 67 , 68 , 69 , 70 ] and in triggering harmful responses in recipient neurons and glial cells [ 71 , 72 ]. On the other hand, they have been also described as vehicles of pro-regenerative molecules, promoting remyelination and brain repair [ 69 , 72 , 73 ].…”

Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Raffaele

Lombardi

Verderio

et al. 2020

Cells

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Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.

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Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease

Cited by 144 publications

References 90 publications

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Neuraxial Cytokines in Pain States

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

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