Aging alters the immunological response to ischemic stroke

Abstract

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.

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

“…This was accompanied by a greater influx of peripheral leukocytes, particularly neutrophils ( Figure 4D), which are the strongest producers of reactive oxygen species (ROS) and matrix metallopeptidases (MMPs) and promote neuronal injury and BBB disruption [124][125][126] . In agreement, an increased number of neutrophils with altered phenotypic responses was previously seen in aged male mice and human stroke patients compared to their younger counterparts 127 and an increased neutrophil to lymphocyte ratio has been associated with stroke severity and outcome 128 . Although the absence of neuroprotective signal in bulk tissue does not rule out the possibility of its presence in individual cell types, these results suggest that an increased neuroinflammation and infiltration of circulating immune cells are one of the primary drivers for the exacerbated pathology in aged mice.…”

“…These results indicate the involvement of other contributors, such as the early-infiltrating peripheral leukocytes. Previously, the hematopoietic component has been identified as a major source of IFN-I signaling following traumatic brain injury 136 and aged mice with bonemarrow transplants from young mice have improved stroke outcome 127 . In concordance, we detected greater upregulation of granulocyte signature genes in aged animals ( Figure 4D).…”

Update of inflammasome activation in microglia/macrophage in aging and aging‐related disease

“…It has been demonstrated that phagocytic capacity is downregulated in senile microglia/macrophage. When hemorrhagic stroke occurs, the inflammatory milieu further limits phagocytic activities of microglia/macrophage, exacerbating disease severity of hemorrhagic stroke . Therefore, aging is an independent risk factor of both ischemic and hemorrhagic stroke and indicates detrimental disease outcomes .…”

“…When hemorrhagic stroke occurs, the inflammatory milieu further limits phagocytic activities of microglia/ macrophage, exacerbating disease severity of hemorrhagic stroke. 56 Therefore, aging is an independent risk factor of both ischemic and hemorrhagic stroke and indicates detrimental disease outcomes. 57 On the other hand, prognosis of stroke is largely dependent on the intensity of post-stroke neural inflammation.…”

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors

“…Although the function of BM-derived Iba1 + cells remains unclear, these cells have recently been attributed towards tissue repair and restoration of function following injury [23,24]. Interestingly, these beneficial effects are only observed when animals are recipients of young BM, but not old, presumably because old BM cells acquire a senescent-like phenotype upon migration to the injured brain [25]. Here, we hypothesize that the introduction of young microglia into the aged and irradiated brain may be beneficial for attenuating cognitive decline following radiotherapy.…”