Ischemic stroke is a major cause of mortality and disability worldwide. Age and sex play a significant role in stroke pathophysiology and outcome, with elderly women showing higher mortality and poorer functional outcomes compared to age-matched men. As the peripheral immune response is known to contribute to secondary tissue damage and infarct evolution up to 24 hours after stroke, early targeting of these cells has become an area of major therapeutic interest. The neutrophil response to ischemic stroke is early and robust, and has been shown to be responsible for a significant portion of this tissue damage. Bone marrow transplant from aged male mice to young male mice increases the infiltration of neutrophils into the brain after stroke and worsens functional outcome. Importantly, these aged brain-infiltrating neutrophils were also found to have an enhanced ?pro-inflammatory phenotype?, characterized by increased production of tissue-damaging reactive oxygen species and matrix metalloproteinase 9. Interestingly, women display a more robust immune response to inflammatory challenge, a phenomenon that has recently been suggested to persist throughout the lifespan. However, no experiments on sex differences in the post-stroke neutrophil response in aged mice have been conducted to date. Preliminary data shows that despite a similar increase in the number of circulating neutrophils, female stroke patients show enhanced neutrophil-specific gene expression at 24 hours than males, independent of stroke severity or age. Given this data, we hypothesize that both age AND sex influence the pro-inflammatory phenotype of brain infiltrating neutrophils after stroke, with aged female animals possessing the highest pro- inflammatory neutrophil response. In this proposal, we aim to determine the influence of sex on timing and inflammatory phenotype of the early neutrophil response to inflammatory challenge. We will also assess whether early depletion of neutrophils after stroke with an anti-Ly6G depleting antibody can reduce neutrophil activation and infiltration into the brain, resulting in reduced tissue damage and improved functional/behavioral outcomes. When completed, this proposal will provide novel insight into the influence of sex on neutrophil phenotype, function, signaling and trafficking in response to ischemic injury. In addition, it will also assess whether specific, post-stroke depletion of neutrophils reduces tissue damage and improves functional outcome after ischemic stroke in young and aged mice of both sexes. This work will also provide the PI with the necessary training to become a productive, innovative future physician-scientist.
Patient heterogeneity represents a major challenge in the treatment of ischemic stroke. Specifically, there are profound age and sex differences in stroke pathology, with elderly female patients experiencing higher mortality and poorer outcome after stroke then males. The peripheral neutrophil response to ischemic stroke is known to result in secondary tissue damage and infarct expansion, and many neutrophil-targeting therapies have been successful in improving outcome in preclinical studies of ischemic stroke. As innate immune cells from elderly female patients have been shown to respond more robustly to inflammatory challenge, and aged bone marrow worsens stroke outcome in mice, the early neutrophil response may contribute to the sex differences in stroke outcome seen in aged populations. In this study, we will determine the influence of sex on the neutrophil response to ischemia, and examine whether neutrophil signaling inhibition reduces tissue damage and improves long-term functional outcome in an aged mouse model of ischemic stroke.
| Ahnstedt, Hilda; Roy-O'Reilly, Meaghan; Spychala, Monica S et al. (2018) Sex Differences in Adipose Tissue CD8+ T Cells and Regulatory T Cells in Middle-Aged Mice. Front Immunol 9:659 |
| Zhao, Xiurong; Ting, Shun-Ming; Sun, Guanghua et al. (2018) Beneficial Role of Neutrophils Through Function of Lactoferrin After Intracerebral Hemorrhage. Stroke 49:1241-1247 |
| Roy-O'Reilly, Meaghan; Zhu, Liang; Atadja, Louise et al. (2017) Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema. Ann Clin Transl Neurol 4:793-800 |
| Roy-O'Reilly, Meaghan; McCullough, Louise D (2017) Astrocytes fuel the fire of lymphocyte toxicity after stroke. Proc Natl Acad Sci U S A 114:425-427 |
| Zhao, Xiurong; Ting, Shun-Ming; Liu, Chin-Hsuan et al. (2017) Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nat Commun 8:602 |
| Roy-O'Reilly, Meaghan; Ritzel, Rodney M; Conway, Sarah E et al. (2017) CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke. Transl Stroke Res 8:578-584 |
