Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits

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Abstract

Background

Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation.

Methods

Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed.

Results

The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits.

Conclusions

Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits.

Electronic supplementary material

The online version of this article (doi:10.1186/s12974-016-0671-y) contains supplementary material, which is available to authorized users.

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Most cited references 39

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Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.

Alexander Mildner, Hauke Schmidt, Mirko Nitsche … (2007)

Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

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Irradiation induces neural precursor-cell dysfunction.

Michelle Monje, Shinichiro Mizumatsu, John Fike … (2002)

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.

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Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects.

X.-M. Dai (2002)

The effects of colony-stimulating factor 1 (CSF-1), the primary regulator of mononuclear phagocyte production, are thought to be mediated by the CSF-1 receptor (CSF-1R), encoded by the c-fms proto-oncogene. To investigate the in vivo specificity of CSF-1 for the CSF-1R, the mouse Csf1r gene was inactivated. The phenotype of Csf1(-)/Csf1r(-) mice closely resembled the phenotype of CSF-1-nullizygous (Csf1(op)/Csf1(op)) mice, including the osteopetrotic, hematopoietic, tissue macrophage, and reproductive phenotypes. Compared with their wild-type littermates, splenic erythroid burst-forming unit and high-proliferative potential colony-forming cell levels in both Csf1(op)/Csf1(op) and Csf1(-)/Csf1r(-) mice were significantly elevated, consistent with a negative regulatory role of CSF-1 in erythropoiesis and the maintenance of primitive hematopoietic progenitor cells. The circulating CSF-1 concentration in Csf1r(-)/Csf1r(-) mice was elevated 20-fold, in agreement with the previously reported clearance of circulating CSF-1 by CSF-1R-mediated endocytosis and intracellular destruction. Despite their overall similarity, several phenotypic characteristics of the Csf1r(-)/Csf1r(-) mice were more severe than those of the Csf1(op)/Csf1(op) mice. The results indicate that all of the effects of CSF-1 are mediated via the CSF-1R, but that subtle effects of the CSF-1R could result from its CSF-1-independent activation.

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Author and article information

Contributors

Xi Feng: xi.feng@ucsf.edu

Timothy D. Jopson: timothy.jopson@ucsf.edu

Maria Serena Paladini: paladini.mariaserena@gmail.com

Sharon Liu: Sharon.liu@ucsf.edu

Brian L. West: bwest@plexxikon.com

Nalin Gupta: Nalin.gupta@ucsf.edu

Susanna Rosi: susanna.rosi@ucsf.edu

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 30 August 2016

Publication date PMC-release: 30 August 2016

Publication date Collection: 2016

Volume: 13

Issue: 1

Electronic Location Identifier: 215

Affiliations

[1 ]Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA 94110 USA

[2 ]Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA USA

[3 ]Department of Neurological Surgery, University of California, San Francisco, CA USA

[4 ]Plexxikon Inc, Berkeley, CA USA

[5 ]Department of Pediatrics, University of California, San Francisco, CA USA

Article

Publisher ID: 671

DOI: 10.1186/s12974-016-0671-y

PMC ID: 5006433

PubMed ID: 27576527

SO-VID: 1e0de7d3-6ec1-4617-a718-59bd5c204dd1

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 April 2016

Date accepted : 17 August 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: R01 CA133216

Award Recipient : Susanna Rosi

Funded by: FundRef http://dx.doi.org/10.13039/100001794, Pediatric Brain Tumor Foundation;

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ScienceOpen disciplines: Neurosciences

Keywords: csf-1r,whole-brain irradiation,cognition

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ScienceOpen disciplines: Neurosciences

Keywords: csf-1r, whole-brain irradiation, cognition

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Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Neuronal Signaling

Most cited references 39

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.

Irradiation induces neural precursor-cell dysfunction.

Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects.

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Cited by 32

Most referenced authors 645