Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Han, Jinming; Chiţu, Violeta; Stanley, E. Richard; Wszołek, Zbigniew K.; Karrenbauer, Virginija Danylaité; Harris, Robert A.

doi:10.1007/s00018-022-04225-1

Cited by 90 publications

(31 citation statements)

References 172 publications

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“…A timely report by Han et al shows inhibition of CSF-1R as a potential therapeutic strategy for white matter disorders in the cases of neurodegenerative diseases [ 32 ]. However, it is uncertain whether CSF-IR inhibitors can act as a prophylactic agent in toxic leukoencephalopathy such as chemobrain, since they only reduce the number of microglia.…”

Section: Discussionmentioning

confidence: 99%

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate

Lim

Kim

et al. 2022

BMC Neurol

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Background The objective of this report is to share the clinicopathological features of chemotherapy-induced toxic leukoencephalopathy, which is a rare and under-recognized disease, clinically characterized by rapidly progressive cognitive loss that often leads to sudden death. Case presentation A 64-year-old woman and a 63-year-old man, who had both suffered from a rapid deterioration of consciousness, were autopsied under the clinical impressions of either the central nervous system graft versus host disease (CNS-GVHD), infectious encephalitis, or autoimmune encephalitis. Both patients had been treated with multiple chemotherapy regimens, including adriamycin, cytarabine arabinoside, daunorubicin, fludarabine, azacitidine, and allogeneic peripheral blood stem cell transplantation to treat hematological malignancies (acute myelogenous leukemia and myelodysplastic syndrome). Neuropathological findings at autopsy revealed rarefaction and vacuolar changes of the white matter with axonal spheroids, reactive gliosis, and foamy macrophage infiltration, predominantly in the visual pathways of the occipital and temporal lobes. Damaged axons exhibited immunoreactivity to beta-amyloid, consistent with axonopathy. However, there was no lymphocyte infiltration that suggested CNS-GVHD or any type of encephalitis. Conclusion The neuropathology found in the presented cases had the characteristic features of toxic leukoencephalopathy (chemobrain). Our cases showed that toxic leukoencephalopathy can also be caused by chemotherapy drugs other than methotrexate.

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Section: Discussionmentioning

confidence: 99%

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate

Lim

Kim

et al. 2022

BMC Neurol

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“…Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling in patients with HDLS has revealed that CSF1R mutations can result in the loss of microglial homeostatic phenotype (M0) in the white matter ( Kempthorne et al, 2020 ). Inhibition of CSF1R has been shown to lead to a partial loss of CSF1 signaling, and a phenotypic shift in the microglia from anti-inflammatory/homeostatic to pro-inflammatory/activated ( Han et al, 2022 ). It is speculated that the signal intensity may arise from fluid trapped between the degenerating layers of myelin sheaths ( Tokumaru et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

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“…Osteoclast-mediated bone resorption is essential for skeletal development and normal bone remodeling. In animal models of arthritis, blocking the activation of CSF-1R with CSF-1R inhibitors like Ki20227 [ 187 ], AFS98 [ 188 ], and GW2580 [ 189 ] slows the progression of joint inflammation and systemic bone erosion (Fig. 4 ) (Table 4 ).…”

Section: Colony-stimulating Factor-1 and Macrophage Differentiationmentioning

confidence: 99%

Macrophage subsets and their role: co-relation with colony-stimulating factor-1 receptor and clinical relevance

et al. 2022

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Macrophages are one of the first innate immune cells to reach the site of infection or injury. Diverse functions from the uptake of pathogen or antigen, its killing, and presentation, the release of pro- or anti-inflammatory cytokines, activation of adaptive immune cells, clearing off tissue debris, tissue repair, and maintenance of tissue homeostasis have been attributed to macrophages. Besides tissue-resident macrophages, the circulating macrophages are recruited to different tissues to get activated. These are highly plastic cells, showing a spectrum of phenotypes depending on the stimulus received from their immediate environment. The macrophage differentiation requires colony-stimulating factor-1 (CSF-1) or macrophage colony-stimulating factor (M-CSF), colony-stimulating factor-2 (CSF-2), or granulocyte–macrophage colony-stimulating factor (GM-CSF) and different stimuli activate them to different phenotypes. The richness of tissue macrophages is precisely controlled via the CSF-1 and CSF-1R axis. In this review, we have given an overview of macrophage origin via hematopoiesis/myelopoiesis, different phenotypes associated with macrophages, their clinical significance, and how they are altered in various diseases. We have specifically focused on the function of CSF-1/CSF-1R signaling in deciding macrophage fate and the outcome of aberrant CSF-1R signaling in relation to macrophage phenotype in different diseases. We further extend the review to briefly discuss the possible strategies to manipulate CSF-1R and its signaling with the recent updates. Graphical Abstract

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Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Cited by 90 publications

References 172 publications

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Macrophage subsets and their role: co-relation with colony-stimulating factor-1 receptor and clinical relevance

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