Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy

Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Bonifazi, P.; Abiega, Oihane; Díaz-Aparicio, Irune; Tegelberg, Saara; Lehesjoki, Anna‐Elina; Valero, Jorge; Sierra, Amanda

doi:10.1111/epi.16692

Cited by 11 publications

(11 citation statements)

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“…Microglia are involved in a broad range of brain functions, including control of neuronal synapse development, normal myelinogenesis or oligodendrocyte progenitor maintenance, phagocytosis of apoptotic cells, and brain repair [52][53][54][55][56][57]. However, their role in bAVM pathology is not yet clear.…”

Section: Discussionmentioning

confidence: 99%

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Park

Kim

Yao

et al. 2022

IJMS

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Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

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Section: Discussionmentioning

confidence: 99%

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Park

Kim

Yao

et al. 2022

IJMS

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“…To what extent the heterogeneity of apoptotic cells plays a role in phagocytosis as well as the possible signaling pathways involved are not yet clear. Such a disturbance has so far only been demonstrated in a temporal lobe epilepsy model (Abiega et al, 2016; Palomba et al, 2021; Sierra‐Torre et al, 2020). In this model, the epileptogenic overexcitation resulted in a strong release of ATP from neurons and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Microglia‐mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke

Rudolph

Schmeer

Günther

et al. 2021

Glia

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Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three‐months‐old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D‐reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory‐ and maladaptive processes including cognitive impairment following stroke needs to be further investigated.

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“…Still, the generation of these seizures may be linked to other microglia-related pathways, including (i) ischemic stroke–which may be due to a microglial response to angiotensin II (see section “Cerebrovascular Disease”), and (ii) mitochondrial dysregulation–which may be caused by an increase in microglial production of ROS ( Nikbakht et al, 2020 ). In mice, excessive extracellular glutamate recruits microglia ( Dissing-Olesen et al, 2014 ; Eyo et al, 2014 , 2018 ), and impairs their phagocytic activity in different epilepsy models ( Abiega et al, 2016 ; Sierra-Torre et al, 2020 ). Both the microglial recruitment and phagocytosis uncoupling in these models were connected to the disruption of ATP signaling ( Eyo et al, 2014 , 2018 ; Abiega et al, 2016 ; Sierra-Torre et al, 2020 ), which, as discussed in sections “Microglia Mediate How the CNS Is Affected by SARS-CoV-2 Infection” and “Microglia Could Determine How the CNS Is Affected by COVID-19 Pathology,” can occur during viral and hypoxic injuries.…”

Section: Microglial-mediated Cns Inflammation May Contribute To the Cmentioning

confidence: 99%

“…In mice, excessive extracellular glutamate recruits microglia ( Dissing-Olesen et al, 2014 ; Eyo et al, 2014 , 2018 ), and impairs their phagocytic activity in different epilepsy models ( Abiega et al, 2016 ; Sierra-Torre et al, 2020 ). Both the microglial recruitment and phagocytosis uncoupling in these models were connected to the disruption of ATP signaling ( Eyo et al, 2014 , 2018 ; Abiega et al, 2016 ; Sierra-Torre et al, 2020 ), which, as discussed in sections “Microglia Mediate How the CNS Is Affected by SARS-CoV-2 Infection” and “Microglia Could Determine How the CNS Is Affected by COVID-19 Pathology,” can occur during viral and hypoxic injuries. Therefore, during COVID-19, not only can microglia contribute to the onset of seizures, but their reparative activity may also be impaired by the SARS-CoV-2-CNS-related insults.…”

Section: Microglial-mediated Cns Inflammation May Contribute To the Cmentioning

confidence: 99%

Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic

Andrade

Šimončičová

Carrier

et al. 2021

Front. Cell. Neurosci.

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Coronavirus disease 2019 (COVID-19) is marked by cardio-respiratory alterations, with increasing reports also indicating neurological and psychiatric symptoms in infected individuals. During COVID-19 pathology, the central nervous system (CNS) is possibly affected by direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion, exaggerated systemic inflammatory responses, or hypoxia. Psychosocial stress imposed by the pandemic further affects the CNS of COVID-19 patients, but also the non-infected population, potentially contributing to the emergence or exacerbation of various neurological or mental health disorders. Microglia are central players of the CNS homeostasis maintenance and inflammatory response that exert their crucial functions in coordination with other CNS cells. During homeostatic challenges to the brain parenchyma, microglia modify their density, morphology, and molecular signature, resulting in the adjustment of their functions. In this review, we discuss how microglia may be involved in the neuroprotective and neurotoxic responses against CNS insults deriving from COVID-19. We examine how these responses may explain, at least partially, the neurological and psychiatric manifestations reported in COVID-19 patients and the general population. Furthermore, we consider how microglia might contribute to increased CNS vulnerability in certain groups, such as aged individuals and people with pre-existing conditions.

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Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 11 publications

References 53 publications

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Microglia‐mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke

Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic

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