Age‐related alterations in the dynamic behavior of microglia

Abstract

SummaryMicroglia, the primary resident immune cells of the central nervous system (CNS), exhibit dynamic behavior involving rapid process motility and cellular migration that is thought to underlie key functions of immune surveillance and tissue repair. Although age-related changes in microglial activation have been implicated in the pathogenesis of neurodegenerative diseases of aging, how dynamic behavior in microglia is influenced by aging is not fully understood. In this study, we employed live imaging of retinal microglia in situ to compare microglial morphology and behavioral dynamics in young and aged animals. We found that aged microglia in the resting state have significantly smaller and less branched dendritic arbors, and also slower process motilities, which probably compromise their ability to survey and interact with their environment continuously. We also found that dynamic microglial responses to injury were age-dependent. While young microglia responded to extracellular ATP, an injury-associated signal, by increasing their motility and becoming more ramified, aged microglia exhibited a contrary response, becoming less dynamic and ramified. In response to laser-induced focal tissue injury, aged microglia demonstrated slower acute responses with lower rates of process motility and cellular migration compared with young microglia. Interestingly, the longer term response of disaggregation from the injury site was retarded in aged microglia, indicating that senescent microglial responses, while slower to initiate, are more sustained. Together, these altered features of microglial behavior at rest and following injury reveal an agedependent dysregulation of immune response in the CNS that may illuminate microglial contributions to agerelated neuroinflammatory degeneration.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Aged microglia have an increased proinflammatory response and shift toward the M1 phenotype. Basal and stimulated secretion of TNF-α and IL-6 were increased in the ex vivo culture of senescent microglia [203], and hypertrophic morphological changes in the aged cells were observed [197,204,205]. Consistent with this evidence, an in vivo study showed that iNOS, TNF-α, and IL-6 were elevated, while arginase-1 was repressed in the midbrain of aged mice [206].…”

“…The primed microglia increased inflammation and leukocyte recruitment in the brain following stroke [196]. Comparing mononuclear phagocytes between young and old mice, aged macrophages, and microglia exhibited reduced motility in response to laser-induced injury and extracellular ATP [197]. In demyelinating models, reduced migration of mononuclear cells [198], and impaired clearance of myelin debris in macrophages accompanied by an age-associated delay in remyelination have been observed [199][200][201].…”

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

“…As a result, reactive microglia releases pro-inflammatory cytokines and neurotoxic factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and reactive oxygen species, the excessive production of which may trigger or exacerbate neuronal death (Liao et al, 2012;Zhang et al, 2011). In addition, some microglial cells become increasingly dysfunctional as they age, and may participate directly in the development of secondary tissue injury and neurodegeneration (Damani et al, 2011;Liao et al, 2012). Therefore, control of microglial activation should bring therapeutic benefit for any central disorder related with neuroinflammation.…”

Mikroglia und Immuntherapien bei degenerativen Netzhauterkrankungen

“…3a). Durch ihr dynamisches Verhalten ist die Mikrogliapopulation in der Lage, in kürzester Zeit eine umfassende Überwa-chung der gesamten Retina zu erreichen [13]. Mikrogliazellen überwachen ihre Umgebung mit einem Repertoire von Oberflächenproteinen für Zytokine, Chemokine, Komplementkomponenten, Antikörper und besonderen Rezeptoren für veränderte Zelloberflächenstruktu-ren.…”