Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.
microglia; neuroprotection; Parkinson's disease; proliferation
Increased pro‐inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor‐1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF‐1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub‐chronic LPS treatment, mRNA and protein levels of CSF1R and CSF‐1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP‐induced CSF1R activation and Iba1‐positive cell proliferation, without a reduction of the basal Iba1‐positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro‐inflammatory factors, without alteration of anti‐inflammatory mediators, and significantly attenuated the MPTP‐induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro‐inflammatory signaling, but maintains the beneficial effects of microglia. [ABSTRACT FROM AUTHOR]
Neal Matthew L; Fleming Sheila M; Budge Kevin M; Boyle Alexa M; Kim Chunki; Alam Gelareh; Beier Eric E; Wu Long‐Jun; Richardson Jason R
FASEB Journal
2020
2020-01
Journal Article
<a href="http://doi.org/10.1096/fj.201900567RR" target="_blank" rel="noreferrer noopener">10.1096/fj.201900567RR</a>
Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide.
Animals; Astrocytes/immunology/pathology; Cell Death/physiology; Corpus Striatum/immunology/pathology; Cytokines/metabolism; Disease Progression; Dopaminergic Neurons/*immunology/pathology; Inbred C57BL; Inflammation/pathology/physiopathology; Lipopolysaccharides/*toxicity; Male; Messenger/metabolism; Mice; Microglia/*immunology/pathology; Nerve Degeneration/*immunology/pathology; Neurodegenerative Diseases/immunology/pathology; Neuroimmunomodulation/physiology; Random Allocation; RNA; Time Factors
Inflammation arising from central and/or peripheral sources contributes to the pathogenesis of multiple neurodegenerative diseases including Parkinson's disease (PD). Emerging data suggest that differential activation of glia could lead to the pathogenesis and progression of PD. Here, we sought to determine the relationship between lipopolysaccharide (LPS) treatment, loss of dopaminergic neurons and differential activation of glia. Using a model of repeated injections with LPS (1mg/kg, i.p. for 4days), we found that LPS induced a 34% loss of dopamine neurons in the substantia nigra 19days after initiation of treatment, but no further cell loss was observed at 36days. LPS induced a strong pro-inflammatory response with increased mRNA expression of pro-inflammatory markers, including tumor necrosis factor-alpha (4.8-fold), inducible nitric oxide synthase (2.0-fold), interleukin-1 beta (8.9-fold), interleukin-6 (10.7-fold), and robust glial activation were observed at 1day after final dose of LPS. These pro-inflammatory genes were then reduced at 19days after treatment, when there was a rise in the anti-inflammatory genes Ym1 (1.8-fold) and arginase-1 (2.6-fold). Additionally, 36days after the last LPS injection there was a significant increase in interleukin-10 (2.1-fold) expression. The qPCR data results were supported by protein data, including cytokine measurements, western blotting, and immunofluorescence in brain microglia. Taken together, these data demonstrate that progressive neurodegeneration in the substantia nigra following LPS is likely arrested by microglia shifting to an anti-inflammatory phenotype. Thus, strategies to promote resolution of neuroinflammation may be a promising avenue to slow the progressive loss of dopamine neurons in PD.
Beier Eric E; Neal Matthew; Alam Gelerah; Edler Melissa; Wu Long-Jun; Richardson Jason R
Neurobiology of disease
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.nbd.2017.08.009" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2017.08.009</a>