To Kill a Microglia: A Case for CSF1R Inhibitors

Green, Kim N.; Crapser, Joshua; Hohsfield, Lindsay A.

doi:10.1016/j.it.2020.07.001

Cited by 168 publications

(164 citation statements)

References 128 publications

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“…We reject the comment by Green and Hume ( 4 ) that PLX5622 dose and duration was not provided or that it was selected arbitrarily. A careful reading of our paper ( 1 ) and the literature reveals this information, which is in concordance with at least 14 papers using exactly the same dose (PLX5622 chow, 1,200 ppm) and duration (3 wk) ( 1 – 3 , 5 ), some of which have been cited by Green et al ( 6 ) in a prior review. † For the benefit of the community, we provide additional data in this Reply showing that even short-term (7 d or 10 d) treatment with PLX5622 results in similar nonmicroglia changes ( Figs.…”

supporting

confidence: 83%

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

Lei

Cui

Zhou

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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supporting

confidence: 83%

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

Lei

Cui

Zhou

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Based upon mouse studies, microglia have been ascribed essential function in embryonic and early postnatal development of the brain, including elimination of dying cells, synaptic remodeling and the development of specific neurons, neurogenic progenitors, oligodendrocytes and the microvasculature (reviewed in Bohlen et al, 2019 ; Green et al, 2020 ; Prinz et al, 2019 ; Smith and Dragunow, 2014 ). Male and female mice and rats have been reported to display differences in microglia number and gene expression ( Guneykaya et al, 2018 ; Osborne et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…The analysis of the brains of homozygous Csf1rko rats revealed remarkably little impact on normal architecture and development given the many functions attributed to microglia ( Green et al, 2020 ; Prinz et al, 2019 ). Expression profiling of brain regions ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations

Patkar

Caruso

Teakle

et al. 2021

Neurobiology of Disease

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Mutations in the human CSF1R gene have been associated with dominant and recessive forms of neurodegenerative disease. Here we describe the impacts of Csf1r mutation in the rat on development of the brain. Diffusion imaging indicated small reductions in major fiber tracts that may be associated in part with ventricular enlargement. RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats. There was no evidence of region or sex-specific expression of microglia-associated transcripts. Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster. Expression of markers of oligodendrocytes, astrocytes, dopaminergic neurons and Purkinje cells was minimally affected. However, there were defects in dendritic arborization of doublecortin-positive neurogenic precursors and expression of poly-sialylated neural cell adhesion molecule (PS-NCAM) in the dentate gyrus of the hippocampus. Heterozygous Csf1rko rats had no detectable brain phenotype. We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy.

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“…CSF1R is principally expressed by microglia in the intact CNS [45][46][47]. Therefore, we cannot exclude that GW2580 treatment may likewise have off-target effects and could affect neurons that also express CSF1R [48] or infiltrating macrophages [for review see [15]]. However, SCI induces a sevenfold greater microglia proliferation as compared to infiltrating macrophages [5] In vivo, evidence of a neuroprotective role of proliferating microglia that may serve as an endogenous pool of neurotrophic molecules such as IGF-1 had been reported in cerebral ischemia [49].…”

Section: Discussionmentioning

confidence: 99%

“…CSF1R inhibition triggers microglial demise in vitro and in vivo [for review see [8]]. Recent studies have targeted CSF1R to modulate neuroinflammatory response in physiological [9,10] and multiple neuro-pathological conditions [11][12][13][14] [for review see [15,16]]. PLX5622 is a CSF1R inhibitor that eradicates selectively and almost entirely microglia.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

Poulen

Aloy

Bringuier

et al. 2021

Preprint

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No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery. In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor. First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity. Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value. Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment. Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

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To Kill a Microglia: A Case for CSF1R Inhibitors

Cited by 168 publications

References 128 publications

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations

Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

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