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REVIEW ARTICLE
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 180-182

Colony stimulating factor-1 receptor as a treatment for cognitive deficits postfractionated whole-brain irradiation


Department of Neurological Surgery, Brain and Spinal Injury Center, University of California, San Francisco, CA, USA

Date of Submission05-Aug-2017
Date of Decision05-Sep-2017
Date of Acceptance05-Sep-2017
Date of Web Publication12-Oct-2017

Correspondence Address:
Susanna Rosi
Brain and Spinal Injury Center Departments of Physical Therapy Rehabilitation Science, Neurological Surgery University of California San Francisco Zuckerberg San Francisco General Hospital 1001 Potrero Ave, Bld#1, Room#101 94110, San Francisco
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bc.bc_25_17

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  Abstract 


Whole-brain irradiation (WBI) is commonly used to treat primary tumors of the central nervous systems tumors as well as brain metastases. While this technique has increased survival among brain tumor patients, the side effects of including a decline in cognitive abilities that are generally progressive. In an effort to combat WBI side effects, researchers explored the treatment of colony stimulating factor-1 receptor (CSF-1R) inhibitor. Data show that when a CSF-1R inhibitor is administered with fractionated WBI treatment, there is a decline in the number of resident and peripheral mononuclear phagocytes, a decrease in dendritic spine loss and a reduction in functional and memory deficits. CSFR-1R inhibitors have displayed promising results as an effective counter-treatment for WBI-induced deficits. Further research is required to optimize treatment strategies, establish a treatment timeline and gain a better understanding of the long-term side effects of targeting CSF-1R as a treatment strategy for WBI symptoms. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

Keywords: Brain metastases, colony stimulating factor-1 receptor inhibitor, microglia, primary central nervous system tumor, whole brain irradiation


How to cite this article:
Rosi S. Colony stimulating factor-1 receptor as a treatment for cognitive deficits postfractionated whole-brain irradiation. Brain Circ 2017;3:180-2

How to cite this URL:
Rosi S. Colony stimulating factor-1 receptor as a treatment for cognitive deficits postfractionated whole-brain irradiation. Brain Circ [serial online] 2017 [cited 2022 Jan 16];3:180-2. Available from: http://www.braincirculation.org/text.asp?2017/3/3/180/216593



Primary tumors of the central nervous system (CNS) and brain metastases may be treated with whole-brain irradiation (WBI) (often delivered in 25–30 fractions for a total dosage of 55–60 Gy). The novel, enhanced treatments have resulted in lowered mortality rates but increased risks of detrimental side effects. In particular, progressive symptoms related to cognitive function present in approximately 50%–90% of long-term survivors (>6 months) after WBI treatment.[1] There is little treatment available for patients suffering from these cognitive abnormalities, as the cause of them is currently unknown. One dose of 10 Gy WBI causes periphery monocytes to gather in the CNS after 7 days of the single dosage.[2] Similarly, research shows that WBI initiates the actions of immune cells expressing MHCII, CD11c, and CD3.[3] Even though one study[4] did not see monocyte-derived macrophages in the WBI treated adult brain, this may be because of varying sources of radiation or discrepancies in monocyte quantification. This study shows that in combination with a certain colony stimulating factor-1 receptor (CSF-1R), fractionated WBI treatment (fWBI) improves functional outcomes by decreasing the amount of resident and peripherally-derived mononuclear phagocytes and inhibiting the development of memory problems and dendritic spine loss (in mice).[5]


  Modulating Whole-Brain Irradiation-Induced Cognitive Deficits: Microglia or Monocytes? Top


CSF-1 signaling plays a major role in the development and function of mononuclear phagocytes.[6] Because of its receptor, CSF-1R, is expressed on the surface of CNS microglia and periphery monocytes, CSF-1R inhibition affects both cell types. Certain dosages of CSF-1R inhibitors can decrease the amount of microglia in mice. There is a 30%–50% reduction in microglia with a 300 ppm dose of PLX5622, a CSF-1R inhibitor,[5],[7] and a nearly complete elimination (>95%) of microglia with either a 1,200 dose of PLX5622 or a 290 ppm dose of PLX3397 (an inhibitor similar to PLX5622).[8] Both levels of microglial depletion block WBI-induced dendritic spine loss and prevent the development of cognitive disabilities.[5],[9] Dendritic spine loss becomes apparent between 2 weeks and a month (the point where cognition is measured) following fWBI and continues until several months posttreatment.[5],[10] Despite knowing that radiation stimulates microglia and peripherally derived monocytes,[2],[11] it is unclear why WBI and fWBI cause dendritic spine loss. WBI increases the brain's concentration of chemoattractant cytokine CCL2, a molecule that stimulates CNS uptake of peripherally derived CCR2+ monocytes.[12] CCR2 is a chemokine receptor absent from brain microglia[2] and the stimulation of CCR2-CCL2 signaling causes the accumulation of CCR2-expressing monocytes (also known as “inflammatory monocytes”) in the injured tissue. These CCR2-expressing monocytes then transform into macrophages with proinflammatory properties.[13] Conversely, a lack of CCR2 molecules impedes the movement of CCR2+ Ly6Chigh from the bone marrow to the blood stream[14] and reduces the WBI-induced neural and cognitive deficits.[11] Ly6Chigh monocyte concentrations are reduced in the blood by PLX5622 treatment and in the CNS by CSF-1R antagonism, whereas Ly6Clow concentration is not affected.[5] In the peripheral nervous system (PNS), Ly6Chigh differentiate into macrophages or dendritic cells within damaged tissues. It is postulated that in neuroinflammatory models (such as those for traumatic brain injury and multiple sclerosis), Ly6Chigh monocytes regulate inflammatory responses of the CNS and that microglia aid in tissue restoration.[14] Stimulation of these monocytes and microglia possibly enhances neuronal damage post-WBI, but the degree of influence these cells have on neuroinflammation following WBI and fWBI is currently unclear. Additional studies are warranted to examine the specific cell phenotypes mediating the learning and memory performance.


  Colony Stimulating Factor-1 Receptor Inhibition as Potential Therapy to Prevent Whole-Brain Irradiation-Induced Cognitive Deficits Top


While CSF-1R inhibition remains one of the principal ways to treat and prevent cognitive deficits post-WBI treatment, more studies are needed to elucidate the treatment's safety, effectiveness, and mechanism of action. First, the function of CSF-1R signaling differs depending on age. Because CSF-1R is naturally expressed in cortical neurons, immature neurons, neural progenitor cells, and following chemical injury, CSF-1R treatment under these conditions may have a direct effect on neural function.[6] Second, CSF-1R treatment may produce different effects regarding inflammation in the CNS, as well as in the PNS due to monocytes expressing both CSF-1R and CCR2 and microglia expressing only CSF-1R. CSFR-1 inhibition most likely decreases microglia concentration, but its effects on monocytes and peripheral immune responses is widely unknown. PLX5622 treatment caused a nearly 30% reduction in Ly6Chigh monocytes but scarcely affected Ly6Clowmonocytes in humans. Other results display a decrease in nonclassical CD14+ CD16+ monocytes but not the classical CD14+ CD16 monocytes following treatment with the CSF-1R antibody.[15] Small inhibitors opposing the antibody, specificity of the inhibitor and antibody, or varied reactions to CSF-1R inhibition in rodents and humans may cause the discrepancies between the classical and nonclassical monocytes. In addition, little is known about the relationships between CSF-1/CSF-1R and CCL2/CCR2 signaling pathways. Third, cognitive deficits generally appear months to years following WBI treatment. While it is unknown if CSF-1R inhibition during irradiation can prevent chronic cognitive abnormalities, several animal studies displayed CSF-1R inhibition to last between 7 days and 12 weeks. Since macrophages' roles differ depending on their microenvironments, infiltrating monocytes and macrophages may change their function from small scale repair to long-term restoration. More studies need to examine the therapeutic window and long-term effects of CSF-1R treatment. Finally, even though WBI treatment is primarily used on brain tumor patients, the majority of studies focus on normal brains due to the additional treatments brain tumor patients often require. CSF-1R inhibitors may interfere with other treatments and the tumor microenvironment of brain-tumor patients, as CSF-1R inhibition primarily affects tumor related macrophages. Even though over 50% of tumors recur after CSF-1R treatment,[16] the inhibitor also appears to prevent glioma development and interact with the tumor's macrophages.[17] More preclinical studies need to be conducted in brain tumor models to examine cognition following CSF-1R inhibitor treatment.

Acknowledgment

The author would like to thank the technical assistance of Samantha Schimmel.

Financial support and sponsorship

This work was supported by National Institutes of Health (NIH), Grants: R01CA213441; R01CA133216 and the Pediatric Brain Tumor Foundation Institute Grant.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Greene-Schloesser D, Robbins ME. Radiation-induced cognitive impairment–from bench to bedside. Neuro Oncol 2012;14 Suppl 4:iv37-44.  Back to cited text no. 1
    
2.
Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, et al. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci 2015;35:748-60.  Back to cited text no. 2
    
3.
Moravan MJ, Olschowka JA, Williams JP, O'Banion MK. Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat Res 2011;176:459-73.  Back to cited text no. 3
    
4.
Han W, Umekawa T, Zhou K, Zhang XM, Ohshima M, Dominguez CA, et al. Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia. Oncotarget 2016;7:82305-23.  Back to cited text no. 4
    
5.
Feng X, Jopson TD, Paladini MS, Liu S, West BL, Gupta N, et al. Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits. J Neuroinflammation 2016;13:215.  Back to cited text no. 5
    
6.
Chitu V, Gokhan Ş, Nandi S, Mehler MF, Stanley ER. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends Neurosci 2016;39:378-93.  Back to cited text no. 6
    
7.
Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation 2015;12:139.  Back to cited text no. 7
    
8.
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain 2016;139:1265-81.  Back to cited text no. 8
    
9.
Acharya MM, Green KN, Allen BD, Najafi AR, Syage A, Minasyan H, et al. Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep 2016;6:31545.  Back to cited text no. 9
    
10.
Feng X, Rosi S. Targeting colony stimulating factor 1 receptor to prevent cognitive deficits induced by fractionated whole-brain irradiation. Neural Regen Res 2017;12:399-400.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Belarbi K, Jopson T, Arellano C, Fike JR, Rosi S. CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Res 2013;73:1201-10.  Back to cited text no. 11
    
12.
Morganti JM, Jopson TD, Liu S, Gupta N, Rosi S. Cranial irradiation alters the brain's microenvironment and permits CCR2+ macrophage infiltration. PLoS One 2014;9:e93650.  Back to cited text no. 12
    
13.
Prinz M, Priller J. Tickets to the brain: Role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J Neuroimmunol 2010;224:80-4.  Back to cited text no. 13
    
14.
Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 2010;5:e13693.  Back to cited text no. 14
    
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Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014;25:846-59.  Back to cited text no. 15
    
16.
Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 2016;352:aad3018.  Back to cited text no. 16
    
17.
Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013;19:1264-72.  Back to cited text no. 17
    



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