Elimination of microglia improves cognitive function following cranial irradiation

Acharya, Munjal M.; Green, Kim N.; Allen, Barrett D.; Najafi, Allison R.; Syage, Amber R.; Minasyan, Harutyun; Le, Mi T.; Kawashita, Takumi; Giedzinski, Erich; Parihar, Vipan K.; West, Brian L.; Baulch, Janet E.; Limoli, Charles L.

doi:10.1038/srep31545

Cited by 214 publications

(236 citation statements)

References 37 publications

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“…Eye drops of MC were administered once or twice a day from 3 days before to 7 days after NMDA injection ( Figure 3a). PLX3379 (Elmore et al, 2014) and PLX significantly reduce microglial number in the brain (Acharya et al, 2016). PLX3379 (Elmore et al, 2014) and PLX significantly reduce microglial number in the brain (Acharya et al, 2016).…”

Section: Instillation Of MCmentioning

confidence: 94%

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

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Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1‐tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up‐regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up‐regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA‐induced degeneration of RGCs, suggesting an importance of non‐cell‐autonomous mechanism in the retinal neuronal excitotoxicity.

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Section: Instillation Of MCmentioning

confidence: 94%

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

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“…In one of our previous studies, we have indicated that cranial irradiation can cause transient accumulation of microglial cells followed by persistent inflammation and pronounced expression of IL‐1β and CCL2 in the hippocampus (Han et al, ). Indeed, neuroinflammation induced by activated resident microglia as well as infiltrating monocytes plays a pivotal role in hippocampal‐dependent severe cognitive dysfunction after both acute and long‐term irradiation (Feng et al, ) and microglial depletion can ameliorate these cranial radiation‐induced cognitive deficits (Acharya et al, ). Confirmed in another study, PLX5662‐mediated depletion can lead to protection from loss of dendritic spines, reduction of CD11b + Ly6G − Ly6C hi monocytes in the blood, inhibition of monocyte accumulation and ultimately prevention of radiation‐induced cognitive abnormalities (Feng et al, ).…”

Section: Depleting Microglia In Diseases: the Friend In Need May Not mentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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“…Recently, a new compound, PLX5622, which acts as specific dietary inhibitor of colony stimulating factor-1 receptor (CSF1R), a tyrosine kinase transmembrane receptor essential for the survival and activation of monocytes and macrophages in the periphery and microglia in the CNS (Erblich et al, 2011;Hamilton and Achuthan, 2013;Elmore et al, 2014), was shown to efficiently eliminate microglia in mice (Dagher et al, 2015). Similar to the less specific CSF1R inhibitor PLX3397 , PLX5622 has been used to study the role of microglia in several conditions of brain injury (Acharya et al, 2016;Feng reported that microglia depletion by PLX5622 increases virus replication and subsequent mortality in response to intracerebral infection with mouse hepatitis virus (MHV; Wheeler et al, 2018) or flaviviruses (West Nile virus and Japanese encephalitis virus; Seitz et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Waltl

Käufer

Gerhauser

et al. 2018

Brain, Behavior, and Immunity

113

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In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.

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Elimination of microglia improves cognitive function following cranial irradiation

Cited by 214 publications

References 37 publications

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

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