Abstract
Microglia activation and proliferation are hallmarks of many neurodegenerative disorders and may contribute to disease pathogenesis. Neurons actively regulate microglia survival and function, in part by secreting the microglia mitogen interleukin (IL)-34. Both IL-34 and colony stimulating factor (CSF)-1 bind colony stimulating factor receptor (CSFR)1 expressed on microglia. Systemic treatment with central nervous system (CNS) penetrant, CSFR1 antagonists, results in microglia death in a dose dependent matter, while others, such as GW2580, suppress activation during disease states without altering viability. However, it is not known how treatment with non-penetrant CSF1R antagonists, such as GW2580, affect the normal physiology of microglia. To determine how GW2580 affects microglia function, C57BL/6J mice were orally gavaged with vehicle or GW2580 (80mg/kg/d) for 8 days. Body weights and burrowing behavior were measured throughout the experiment. The effects of GW2580 on circulating leukocyte populations, brain microglia morphology, and the transcriptome of magnetically isolated adult brain microglia were determined. Body weights, burrowing behavior, and circulating leukocytes were not affected by treatment. Analysis of Iba-1 stained brain microglia indicated that GW2580 treatment altered morphology, but not cell number. Analysis of RNA-sequencing data indicated that genes related to reactive oxygen species (ROS) regulation and survival were suppressed by treatment. Treatment of primary microglia cultures with GW2580 resulted in a dose-dependent reduction in viability only when the cells were concurrently treated with LPS, an inducer of ROS. Pre-treatment with the ROS inhibitor, YCG063, blocked treatment induced reductions in viability. Finally, GW2580 sensitized microglia to hydrogen peroxide induced cell death. Together, these data suggest that partial CSF1R antagonism may render microglia more susceptible to reactive oxygen and nitrogen species.
Highlights
Microglia comprise 10-15% of total cells in the central nervous system (CNS) and are the recognized resident macrophages of this tissue
Because macrophages and monocytes express Csf1r [56], we questioned whether treatment affected the percentages of circulating immune cells
In the current study we characterized the effects of GW2580, a colonystimulating factor 1 receptor (CSF1R) antagonist, on microglia
Summary
Microglia comprise 10-15% of total cells in the central nervous system (CNS) and are the recognized resident macrophages of this tissue. Microglia function to maintain homeostasis within the healthy brain and act as facilitators of immune responses within the CNS in response to damage or pathogenic challenge. Upon activation by pathogen associated molecular patterns or by damage associated molecular patterns, microglia release cytokines, chemokines [3, 4] as well as cytotoxic substances including reactive oxygen species (ROS), and nitric oxide (NO) [4,5,6]. While the production of inflammatory mediators by microglia may aid in the clearance of pathogens and/or facilitate repair, aberrant microglia activation is suspected to contribute to a plethora of neurological diseases and disorders including multiple sclerosis [7, 8], Alzheimer’s disease [9], stroke [10], Parkinson’s disease [11], amyotrophic lateral sclerosis [12] and autism spectrum disorder [13, 14]. Proinflammatory cytokine production within the CNS is thought to contribute to sickness behavior [15, 16] and impaired cognitive function [15, 17,18,19]
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