Aging‐like changes in the transcriptome of irradiated microglia

Li, Matthew; Burns, Terry C.; Kumar, Sunil; Morgan, Alexander A.; Sloan, Steven A.; Palmer, Theo D.

doi:10.1002/glia.22782

Cited by 46 publications

(47 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is unlikely as the rejuvenation (i.e., Young → Old) and age-acceleration (i.e., Old → Young) patterns pertaining to brain production of cytokines and growth factors [57, 76], microglia phagocytosis [65], locomotor activity and coordination [23, 24], emotional behavior [13, 27, 87], and other features of frailty [49] are highly consistent with the literature in aging research. Despite these findings, it is worth noting that significant interactions between age and irradiation in microglia activation have been demonstrated by others [36, 45, 73]. Additionally, chronic time points are required to understand how this acute neutrophil response can affect delayed lymphocyte recruitment, recovery, cognitive function, and glial scar formation [20].…”

Section: Discussionmentioning

confidence: 99%

Aging alters the immunological response to ischemic stroke

et al. 2018

View full text Add to dashboard Cite

The peripheral immune system plays a critical role in aging and in the response to brain injury. Emerging data suggest inflammatory responses are exacerbated in older animals following ischemic stroke; however, our understanding of these age-related changes is poor. In this work, we demonstrate marked differences in the composition of circulating and infiltrating leukocytes recruited to the ischemic brain of old male mice after stroke compared to young male mice. Blood neutrophilia and neutrophil invasion into the brain were increased in aged animals. Relative to infiltrating monocyte populations, brain-invading neutrophils had reduced phagocytic potential, and produced higher levels of reactive oxygen species and extracellular matrix-degrading enzymes (i.e., MMP-9), which were further exacerbated with age. Hemorrhagic transformation was more pronounced in aged versus young mice relative to infarct size. High numbers of myeloperoxidase-positive neutrophils were found in postmortem human brain samples of old (> 71 years) acute ischemic stroke subjects compared to non-ischemic controls. Many of these neutrophils were found in the brain parenchyma. A large proportion of these neutrophils expressed MMP-9 and positively correlated with hemorrhage and hyperemia. MMP-9 expression and hemorrhagic transformation after stroke increased with age. These changes in the myeloid response to stroke with age led us to hypothesize that the bone marrow response to stroke is altered with age, which could be important for the development of effective therapies targeting the immune response. We generated heterochronic bone marrow chimeras as a tool to determine the contribution of peripheral immune senescence to age- and stroke-induced inflammation. Old hosts that received young bone marrow (i.e., Young → Old) had attenuation of age-related reductions in bFGF and VEGF and showed improved locomotor activity and gait dynamics compared to isochronic (Old → Old) controls. Microglia in young heterochronic mice (Old → Young) developed a senescent-like phenotype. After stroke, aged animals reconstituted with young marrow had reduced behavioral deficits compared to isochronic controls, and had significantly fewer brain-infiltrating neutrophils. Increased rates of hemorrhagic transformation were seen in young mice reconstituted with aged bone marrow. This work suggests that age alters the immunological response to stroke, and that this can be reversed by manipulation of the peripheral immune cells in the bone marrow.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1859-2) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Aging alters the immunological response to ischemic stroke

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Persistent neuroinflammation caused by cranial irradiation has been established in immune‐competent mouse brain . Moravan et al showed that cranial irradiation results in a multiphasic inflammatory response that includes delayed infiltration of immune cells in the brains of immune‐competent mice.…”

Section: Discussionmentioning

confidence: 99%

“…RT was also sufficient to induce the migration of peripherally derived macrophages into the brain, and was suggested to be an attempt at replacing depleted resident microglia. Others have shown that selective depletion in resident microglia results in the recruitment, infiltration and engraftment of peripheral macrophages into the brain . Thus, it is possible that the reduction in F4/80 staining observed in our experimental tumors may be the result of the depletion of microglia caused by our radiation treatment, although further investigation is necessary to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis

Hamilton

Wong

et al. 2018

NMR in Biomedicine

View full text Add to dashboard Cite

Whole‐brain radiotherapy is the standard of care for patients with breast cancer with multiple brain metastases and, although this treatment has been essential in the management of existing brain tumors, there are many known negative consequences associated with the irradiation of normal brain tissue. In our study, we used in vivo magnetic resonance imaging analysis to investigate the influence of radiotherapy‐induced damage of healthy brain on the arrest and growth of metastatic breast cancer cells in a mouse model of breast cancer brain metastasis. We observed that irradiated, but otherwise healthy, neural tissue had an increased propensity to support metastatic growth compared with never‐irradiated controls. The elucidation of the impact of irradiation on normal neural tissue could have implications in clinical patient management, particularly in patients with residual systemic disease or with residual radio‐resistant brain cancer.

show abstract

“…Recent research demonstrates that defective microglial-mediated synaptic pruning can be associated with social deficits and behaviors resembling neuropsychiatric disorders [12]. Radiation treatment has been shown to induce inflammatory microglia [13–17, 18], and microglia in this inflammatory state can impair synaptic pruning [17]. While prior studies have focused on the deleterious effects of radiation-induced neuroinflammation on hippocampal neurogenesis [13, 14], the impairment of normal synaptic pruning by radiation proposed here suggests that additional, novel therapeutic strategies may mitigate neurocognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Chemoradiation impairs normal developmental cortical thinning in medulloblastoma

Kundu

Durkee

et al. 2017

J Neurooncol

Self Cite

View full text Add to dashboard Cite

Medulloblastoma patients are treated with surgery, radiation and chemotherapy. Radiation dose to the temporal lobe may be associated with neurocognitive sequelae. Longitudinal changes of temporal lobe cortical thickness may result from neurodevelopmental processes such as synaptic pruning. This study applies longitudinal image analysis to compare developmental change in cortical thickness in medulloblastoma (MB) patients who were treated by combined modality therapy to that of cerebellar juvenile pilocytic astrocytoma (JPA) patients who were treated by surgery alone. We hypothesized that the rates of developmental change in cortical thickness would differ between these two groups. This retrospective cohort study assessed changes in cortical thickness over time between MB and JPA patients. High-resolution magnetic resonance (MR) images of 14 MB and 7 JPA subjects were processed to measure cortical thickness of bilateral temporal lobe substructures. A linear mixed effects model was used to identify differences in substructure longitudinal changes in cortical thickness. The left temporal lobe exhibited overall increased cortical thickness in MB patients relative to JPA patients who showed overall cortical thinning (mean annual cortical thickness change: MB 0.14 mm/year versus JPA −0.018 mm/year across all substructures), particularly in the inferior temporal lobe substructures (p < 0.0001). The cortical thickness change of the right temporal lobe substructures exhibited similar, though attenuated trends (p = 0.002). MB patients exhibit overall increased cortical thickness rather than cortical thinning as seen in JPA patients and as expected in normal cortical development. These observations are possibly due to chemoradiation induced-disruption of normal neuronal mechanisms. Longitudinal image analysis may identify early biomarkers for neurocognitive function with routine imaging.

show abstract

Aging‐like changes in the transcriptome of irradiated microglia

Cited by 46 publications

References 74 publications

Aging alters the immunological response to ischemic stroke

Aging alters the immunological response to ischemic stroke

Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis

Chemoradiation impairs normal developmental cortical thinning in medulloblastoma

Contact Info

Product

Resources

About