CSF1R inhibition by a small molecule inhibitor affects hematopoiesis and the function of macrophages

Lei, Fengyang; Cui, Naiwen; Zhou, Chengxin; Chodosh, James; Vavvas, Demetrios G.; Paschalis, Eleftherios I.

doi:10.1101/2019.12.27.889469

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…These "control" mice we refer to as "microglia sufficient" mice. Interestingly, although PLX5622 was recently shown to reduce lymphoid and myeloid cell numbers with a 3-week treatment (Lei et al, 2020;Spiteri et al, 2022), we speculated that the prolonged treatment regimen could have yielded this result. Therefore, we used PLX at a high concentration (660 mg/kg) to facilitate rapid microglial cell elimination.…”

Section: Pharmacological Microglial Elimination and Repopulationmentioning

confidence: 89%

Microglia play beneficial roles in multiple experimental seizure models

Gibbs-Shelton

Benderoth

Gaykema

et al. 2023

Glia

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Seizure disorders are common, affecting both the young and the old. Currently available antiseizure drugs are ineffective in a third of patients and have been developed with a focus on known neurocentric mechanisms, raising the need for investigations into alternative and complementary mechanisms that contribute to seizure generation or its containment. Neuroinflammation, broadly defined as the activation of immune cells and molecules in the central nervous system (CNS), has been proposed to facilitate seizure generation, although the specific cells involved in these processes remain inadequately understood. The role of microglia, the primary inflammation-competent cells of the brain, is debated since previous studies were conducted using approaches that were less specific to microglia or had inherent confounds. Using a selective approach to target microglia without such side effects, we show a broadly beneficial role for microglia in limiting chemoconvulsive, electrical, and hyperthermic seizures and argue for a further understanding of microglial contributions to contain seizures.

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Section: Pharmacological Microglial Elimination and Repopulationmentioning

confidence: 89%

Microglia play beneficial roles in multiple experimental seizure models

Gibbs-Shelton

Benderoth

Gaykema

et al. 2023

Glia

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“…Although CSF1R inhibitors primarily deplete microglia, they can target other peripheral immune cells. Monocyte and macrophage subsets express CSF1R and can be vulnerable to depletion (Lei et al, 2020). Few studies have investigated the peripheral effects of CSF1R inhibition after TBI.…”

Section: Effect Of Csf1r Inhibition On Peripheral Immune Cellsmentioning

confidence: 99%

Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury

Boland,

Kokiko-Cochran

2024

Front. Cell. Neurosci.

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Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI is often associated with poor outcome. As a result, increased attention has been placed on the role of immune cells in post-injury recovery. Microglia are highly dynamic after TBI and play a key role in the post-injury neuroinflammatory response. Therefore, microglia represent a malleable post-injury target that could substantially influence long-term outcome after TBI. This review highlights the cell specific role of microglia in TBI pathophysiology. Microglia have been manipulated via genetic deletion, drug inhibition, and pharmacological depletion in various pre-clinical TBI models. Notably, colony stimulating factor 1 (CSF1) and its receptor (CSF1R) have gained much traction in recent years as a pharmacological target on microglia. CSF1R is a transmembrane tyrosine kinase receptor that is essential for microglia proliferation, differentiation, and survival. Small molecule inhibitors targeting CSF1R result in a swift and effective depletion of microglia in rodents. Moreover, discontinuation of the inhibitors is sufficient for microglia repopulation. Attention is placed on summarizing studies that incorporate CSF1R inhibition of microglia. Indeed, microglia depletion affects multiple aspects of TBI pathophysiology, including neuroinflammation, oxidative stress, and functional recovery with measurable influence on astrocytes, peripheral immune cells, and neurons. Taken together, the data highlight an important role for microglia in sustaining neuroinflammation and increasing risk of oxidative stress, which lends to neuronal damage and behavioral deficits chronically after TBI. Ultimately, the insights gained from CSF1R depletion of microglia are critical for understanding the temporospatial role that microglia develop in mediating TBI pathophysiology and recovery.

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“…As discussed, the use of CSF1R inhibitors is an emerging technique with demonstrated efficacy in the ablation of microglia in the CNS (Elmore et al, 2014;Fujiwara et al, 2021). The CSF1R inhibitors, such as PLX3397 and PLX5622, are CNS-permeable and selectively inhibit tyrosine kinase receptors on macrophages and microglia, although the specificity of these inhibitors varies depending on the specific compound used (Green et al, 2020;Hupp and Iliev, 2020), with PLX5622 recently shown to exert effects on peripheral bone marrow and tissue-resident macrophages (Lei et al, 2020). CSF1R inhibitors are orally bioavailable, but their routes of administration can also include intravenous or subcutaneous injection (Hupp and Iliev, 2020).…”

Section: Pharmacological Depletion Of Microgliamentioning

confidence: 99%

Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping

Bobotis,

Halvorson,

Carrier

et al. 2024

Front. Cell. Neurosci.

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The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in the maintenance and regulation of neuronal network dynamics. Research on microglia, the resident innate immune cells of the CNS, has advanced considerably in recent years, and our understanding of their diverse functions continues to grow. Microglia play critical roles in the formation and regulation of neuronal synapses, myelination, responses to injury, neurogenesis, inflammation, and many other physiological processes. In parallel with advances in microglial biology, cutting-edge techniques for the characterization of microglial properties have emerged with increasing depth and precision. Labeling tools and reporter models are important for the study of microglial morphology, ultrastructure, and dynamics, but also for microglial isolation, which is required to glean key phenotypic information through single-cell transcriptomics and other emerging approaches. Strategies for selective microglial depletion and modulation can provide novel insights into microglia-targeted treatment strategies in models of neuropsychiatric and neurodegenerative conditions, cancer, and autoimmunity. Finally, fate mapping has emerged as an important tool to answer fundamental questions about microglial biology, including their origin, migration, and proliferation throughout the lifetime of an organism. This review aims to provide a comprehensive discussion of these established and emerging techniques, with applications to the study of microglia in development, homeostasis, and CNS pathologies.

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CSF1R inhibition by a small molecule inhibitor affects hematopoiesis and the function of macrophages

Cited by 7 publications

References 28 publications

Microglia play beneficial roles in multiple experimental seizure models

Microglia play beneficial roles in multiple experimental seizure models

Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury

Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping

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