Pharmacological Depletion of Microglia Leads to a Dose-Dependent Reduction in Inflammation and Senescence in the Aged Murine Brain

• Published in: Neuroscience 2022-04, Vol.488, p.1-9
• Main Authors: Stojiljkovic, Milan R., Schmeer, Christian, Witte, Otto W.
• Format: Article
• Language: English
• Subjects: aging; Animals; Brain - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - pharmacology; depletion; inflammaging; Inflammation - metabolism; Macrophages - metabolism; Mice; microglia; Microglia - metabolism; PLX5622; senescence
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2022.02.018

[Display omitted] •Treatment with PLX5622 leads to a dose-dependent depletion of microglia.•Treatment with PLX5622 differentially affected cytokines in young and aged mice.•Low doses lead to reduction in inflammation circumventing the astrocyte activation.•Depletion of microglia led to decreased expression of the senescence marker p16.•Brain inflammation can be reduced by reducing the microglial cell population. Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-α, IL1-β, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population.