Microglia in steady state

Kierdorf, Katrin; Prinz, Marco

doi:10.1172/jci90602

Cited by 230 publications

(192 citation statements)

References 117 publications

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“…Second, blocking the CSF‐1R may also interfere with the well‐known trophic function of myeloid cells (Pollard, ) as has recently been demonstrated in the context of oligodendrocyte development, myelination, and oligodendrocyte precursor survival (Hagemeyer et al, ). Third, microglial cells are important mediators of synaptic plasticity and homeostasis, reflecting their potential role in higher functions of the CNS, like learning and memory (Kierdorf & Prinz, ). Last, as the CSF‐1R is reportedly also expressed on neuronal precursor and lineage cells and mediates ligand‐stimulated neuronal differentiation and survival, long‐term CSF‐1R blockade may affect features related to neuronal plasticity and behavior (Luo et al, ; Nandi et al, ).…”

Section: Discussionmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

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Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease‐amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS). These mutations cause a loss of function of the gene product resulting in a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation comprising adaptive immune reactions promotes disease progression in these PLP1 mutant models, opening the possibility to improve disease outcome of the respective disorders by targeting/modulating inflammation. We here show that PLX3397, a potent inhibitor of the CSF‐1R and targeting innate immune cells, attenuates neuroinflammation in our models by reducing numbers of resident microglia and attenuating T‐lymphocyte recruitment in the CNS. This leads to an amelioration of demyelination, axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the inner retinal composite layer in longitudinal studies using noninvasive optical coherence tomography. Our findings identify microglia as important promoters of neuroinflammation‐related neural damage and CSF‐1R inhibition as a possible therapeutic strategy not only for PMS but also for inflammation‐related genetic diseases of the nervous system for which causal treatment options are presently lacking.

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Section: Discussionmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

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“…In order to perform these above‐mentioned functions a diverse array of receptors including TAM receptors, glutamate receptors, and purinergic receptors are used by microglia to efficiently communicate with other cells (Fourgeaud et al, ; York, Bernier, & MacVicar, ). Among these complex systems the CX3CL1/CX3CR1 and CD200‐CD200R axes play key roles in microglia–neuron contact (Eyo & Wu, ; Kierdorf & Prinz, ; Limatola & Ransohoff, ; Mecca, Giambanco, Donato, & Arcuri, ). Indeed, the CX3CR1 −/− mouse exhibited profound alterations in both morphology and connectivity of the mature newborn hippocampal granule neurons (Bolos et al, ).…”

Section: Multi‐tasking Microglia: a Friend For Brain Homeostasismentioning

confidence: 99%

“…Microglia have traditionally been considered to be in a resting and quiescent state in physiological conditions. With the advent of elegant two/multiple photon microscopy image techniques, genetic and molecular targeting tools, we now appreciate that in normal conditions microglia have a ramified morphology, are maintained by diverse signals from neurons and can continuously move their dendrites, which allows for constant active screening of the surrounding microenvironment (Kierdorf & Prinz, ; Nimmerjahn, Kirchhoff, & Helmchen, ).…”

Section: Introductionmentioning

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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“…The cellular activities of microglia are diverse, ranging from protective to detrimental depending on cellular "states" defined by the characteristic expression of different sets of signature genes (Keren-Shaul et al, 2017;Krasemann et al, 2017). In the healthy CNS, microglia exhibit a distinct resting or homeostatic state featured by the expression of genes that are vital for the defensive activities of microglia against various disease-associated events (Kierdorf & Prinz, 2017). Upon brain injuries and in the aging brain, or in brains affected by neurodegenerative diseases, the homeostatic state of microglia is lost, accompanied by the induction of disease-associated phenotypes (Butovsky & Weiner, 2018;Keren-Shaul et al, 2017;Krasemann et al, 2017;Zrzavy et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

NG2 glia are required for maintaining microglia homeostatic state

Liu

Aguzzi

2019

Glia

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Microglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms underlying the maintenance of distinct microglia cellular states are largely unclear. Here, we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small‐molecule inhibitors of platelet‐derived growth factor (PDGF) signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease‐associated microglia profiles. Similar findings were also observed in vivo by genetically depleting NG2 glia or conditionally inhibiting NG2 glia PDGF signaling in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient, and selective tool for the investigation of NG2 glia function.

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Microglia in steady state

Cited by 230 publications

References 117 publications

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

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

NG2 glia are required for maintaining microglia homeostatic state

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