Effect of the CSF1R inhibitor PLX3397 on remyelination of corpus callosum in a cuprizone‐induced demyelination mouse model

Tahmasebi, Fatemeh; Pasbakhsh, Parichehr; Mortezaee, Keywan; Madadi, Shabnam; Barati, Shirin; Kashani, Iraj Ragerdi

doi:10.1002/jcb.28344

Cited by 43 publications

(17 citation statements)

References 54 publications

(130 reference statements)

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“…Many studies have interrogated the role of microglial cells in inflammatory diseases of the CNS using a depleting dose of a CSF1R inhibitor. In particular, studies have utilized both the C57BL/6 EAE and cuprizone models to understand the role of microglia and infiltrating macrophages in MS 22,29,50 . Some studies have shown marked improvement in EAE disease score in the presence of a CSF1R inhibitor 29 as well as a blockade of demyelination in the cuprizone model 50 .…”

Section: Discussionmentioning

confidence: 99%

CSF1R signaling is a regulator of pathogenesis in progressive MS

Hagan¹,

Kane²,

Grover³

et al. 2020

Cell Death Dis

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Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1Rinh attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.

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Section: Discussionmentioning

confidence: 99%

CSF1R signaling is a regulator of pathogenesis in progressive MS

Hagan¹,

Kane²,

Grover³

et al. 2020

Cell Death Dis

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“…Inhibition of microglial activation with minocycline in mice undergoing cuprizone treatment reduced demyelination, highlighting the detrimental function of microglia in this model (Skripuletz et al, 2010). Along this line, depletion of microglia by the administration of the CSF1R inhibitor PLX3397 during the remyelination phase resulted in increased remyelination rate and improved recovery of motor deficits (Tahmasebi et al, 2019). Short term treatment with the CSF1R kinase inhibitor BLZ945 also led to reduced microglia numbers which correlated with less demyelination and higher oligodendrocyte numbers in the corpus callosum.…”

Section: Detrimental Microglial Responses In Cuprizone-induced Demyelmentioning

confidence: 79%

Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis

Plastini

Desu

Brambilla

2020

Front. Cell. Neurosci.

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Microglia play an essential role in maintaining central nervous system (CNS) homeostasis, as well as responding to injury and disease. Most neurological disorders feature microglial activation, a process whereby microglia undergo profound morphological and transcriptional changes aimed at containing CNS damage and promoting repair, but often resulting in overt inflammation that sustains and propagates the neurodegenerative process. This is especially evident in multiple sclerosis (MS), were microglial activation and microglia-driven neuroinflammation are considered key events in the onset, progression, and resolution of the disease. Our understanding of microglial functions in MS has widened exponentially in the last decade by way of new tools and

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“…In this context, the study using aging mice showed that repopulation of microglia after elimination by the CSF1R inhibitor restores microglial morphology (repopulated cells resemble young cells) and ameliorates age-related cognitive dysfunction [25]. Other studies indicate that the depletion of microglia also improves neurological deficits in mouse models of demyelination-related diseases, such as catatonia [26] and multiple sclerosis [27,28].…”

Section: Discussionmentioning

confidence: 99%

Depletion of microglia ameliorates white matter injury and cognitive impairment in a mouse chronic cerebral hypoperfusion model

Kakae

Tobori

Morishima

et al. 2019

Biochemical and Biophysical Research Communications

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Microglia are immune cells in the central nervous system (CNS) and essential for homeostasis that are important for both neuroprotection and neurotoxicity, and are activated in a variety of CNS diseases. Microglia aggravate cognitive impairment induced by chronic cerebral hypoperfusion, but their precise roles under these conditions remain unknown. Here, we used PLX3397, a colony-stimulating factor 1 receptor inhibitor, to deplete microglia in mice with chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Cognitive impairment induced 28 days after BCAS was significantly improved in mice fed a diet containing PLX3397. In PLX3397-fed mice, microglia were depleted and white matter injury induced by BCAS was suppressed. In addition, the expression of proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha, was suppressed in PLX3397-fed mice. Taken together, these findings suggest that microglia play destructive roles in the development of cognitive impairment and white matter injury induced by chronic cerebral hypoperfusion. Thus, microglia represent a potential therapeutic target for chronic cerebral hypoperfusion-related diseases.

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Effect of the CSF1R inhibitor PLX3397 on remyelination of corpus callosum in a cuprizone‐induced demyelination mouse model

Cited by 43 publications

References 54 publications

CSF1R signaling is a regulator of pathogenesis in progressive MS

CSF1R signaling is a regulator of pathogenesis in progressive MS

Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis

Depletion of microglia ameliorates white matter injury and cognitive impairment in a mouse chronic cerebral hypoperfusion model

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