Microglia ablation alleviates myelin-associated catatonic signs in mice

Jáňová, Hana; Arinrad, Sahab; Balmuth, Evan; Mitjans, Marina; Hertel, Johannes; Habes, Mohamad; Bittner, Robert A.; Pan, Hong; Goebbels, Sandra; Begemann, Martin; Gerwig, Ulrike C.; Langner, Sönke; Werner, Hauke; Kittel‐Schneider, Sarah; Homuth, Georg; Davatzikos, Christos; Völzke, Henry; West, Brian L.; Reif, Andreas; Grabe, Hans J.; Boretius, Susann; Ehrenreich, Hannelore; Nave, Klaus Armin

doi:10.1172/jci97032

Cited by 103 publications

(118 citation statements)

References 57 publications

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“…In further exploring gene expression changes in non-microglial cells, we found that OPC genes were downregulated by microglial depletion, in line with recent reports that depletion lowers OPC numbers (Hagemeyer et al 2017; Janova et al 2017). However, mature oligodendrocyte-expressed genes were upregulated between Control and Elim (Figure 3E).…”

Section: Resultssupporting

confidence: 87%

“…their specificity to microglia), as well as confirm that their expression has not been switched on/upregulated by the microglial extraction processes used by the prior studies. Interestingly, we found that OPC-expressed genes are decreased with microglial elimination, supporting the findings of recent studies highlighting the role of adult microglia in OPC population maintenance (Hagemeyer et al 2017; Janova et al 2017). However, we also find that oligodendrocyte expressed genes are upregulated at the same time, and lineage tracing from OPC’s (via PDGFRα-cre) showed that overall levels of OPC’s and their descendants (i.e.…”

Section: Discussionsupporting

confidence: 91%

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A limited capacity for microglial repopulation in the adult brain

Najafi

Crapser

Jiang

et al. 2018

Glia

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Microglia are the resident immune cell of the central nervous system (CNS), and serve to protect and maintain the local brain environment. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R); administration of CSF1R inhibitors that cross the blood brain barrier (BBB) lead to the elimination of up to 99% of microglia, depending on CNS exposure and treatment duration. Once microglia are depleted, withdrawal of inhibitor stimulates repopulation of the entire CNS with new cells, conceivably enabling a therapeutic strategy for beneficial renewal of the entire microglial tissue. We have explored the kinetics and limits of this repopulation event and show that the rate of microglial repopulation is proportional to the extent of microglial depletion – greater depletion of microglia results in more rapid repopulation. Using a CSF1R inhibitor formulation that eliminates ~99% of microglia within 7 days, we subjected mice to multiple rounds of elimination (7 days’ treatment) and repopulation (7 days’ recovery) and found that the brain only has the capacity for a single complete repopulation event; subsequent elimination and CSF1R inhibitor withdrawal fail to repopulate the brain. However, if the recovery time between, or after, cycles is extended sufficiently then the brain can ultimately repopulate. These kinetic studies define the opportunities and possible limits of the remarkable renewal capacities of microglia.

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Section: Resultssupporting

confidence: 87%

Section: Discussionsupporting

confidence: 91%

A limited capacity for microglial repopulation in the adult brain

Najafi

Crapser

Jiang

et al. 2018

Glia

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“…Our combined observations are in line with the concept that activated proinflammatory microglia are involved in the recruitment of pathogenic lymphocytes during CNS autoimmunity (Goldmann & Prinz, ; Wu et al, ). In a recent report about a myelin‐related mutant of the CNS displaying clinical features related to catatonia, Cnp1 ‐deficient mice, CSF‐1Ri‐mediated microglial depletion also caused an amelioration of clinical symptoms, concomitant with a reduction of CD3+ T‐lymphocyte numbers in the CNS and an attenuation of axonal damage (Janova et al, ). Although in the Cnp1 ‐deficient mice the pathogenic role of lymphocytes has so far not been investigated experimentally (Wieser et al, ), it is plausible to assume that the beneficial effect of microglial depletion regarding axonal pathology in these mutants is also related to the reduction of T‐lymphocyte numbers, likely of the CD8+ subtype.…”

Section: Discussionmentioning

confidence: 98%

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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“…Furthermore, PLX5562 treatment can also alleviate two different forms of Charcot–Marie–Tooth disease by reducing neuropathic features, axonal damage and promoting hindlimb grip strength (Klein et al, ; Scherer, ). One more study showed that microglial depletion by PLX5562 treatment prevented the symptom of catatonia in structural myelin protein Cnp −/− mouse by reducing neuroinflammation and neurodegeneration (Janova 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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Microglia ablation alleviates myelin-associated catatonic signs in mice

Cited by 103 publications

References 57 publications

A limited capacity for microglial repopulation in the adult brain

A limited capacity for microglial repopulation in the adult brain

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

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