Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide.

Title

Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide.

Creator

Beier Eric E; Neal Matthew; Alam Gelerah; Edler Melissa; Wu Long-Jun; Richardson Jason R

Publisher

Neurobiology of disease

Date

2017
2017-12

Description

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.

Subject

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

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

115–127

Volume

108

Citation

Beier Eric E; Neal Matthew; Alam Gelerah; Edler Melissa; Wu Long-Jun; Richardson Jason R, “Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide.,” NEOMED Bibliography Database, accessed June 21, 2021, https://neomed.omeka.net/items/show/3706.

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