Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke

Dotson, Abby L.; Wang, Jianming; Saugstad, Julie A.; Murphy, Stephanie J.; Offner, Halina

doi:10.1016/j.jneuroim.2014.11.020

Cited by 70 publications

(82 citation statements)

References 37 publications

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“…Accordingly, reduced CD45 hi /CD11b + cells (activated microglia and infiltrated macrophages) in the brain and fewer spleen contractions have been related to the smaller injury in females [166]. Splenectomy was effective in reducing the injury size and CD45 hi /CD11b + cells in the ischemic brain only in male mice, supporting a role for peripheral mononuclear phagocytes to the sex differences in stroke [88]. While most stroke studies exclude female animals owing to the hormonal changes with the estrus cycle, evidence suggests sex as an important biological variable to be addressed in stroke research.…”

Section: Sex-associated Modulation Of Mononuclear Phagocytesmentioning

confidence: 86%

“…Increased apoptosis in the spleen, albeit controversial (see Kim et al [25]), and cell release from the spleen are related to reduced spleen size [26]. Others have also reported that splenectomy or splenic irradiation reduces ischemic injury in animal models of stroke [87][88][89]. While these data provided a rationale for targeting the spleen as a therapeutic strategy for patients with stroke, there are reports that argue against this approach.…”

Section: Monocytes and Monocyte-derived Macrophagesmentioning

confidence: 99%

“…In rodent stroke, premenopausal females exhibit smaller infarct size than age-matched males [88,[165][166][167][168]. However, the risk of stroke is increased as females age [169][170][171][172].…”

Section: Sex-associated Modulation Of Mononuclear Phagocytesmentioning

confidence: 99%

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Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Section: Sex-associated Modulation Of Mononuclear Phagocytesmentioning

confidence: 86%

Section: Monocytes and Monocyte-derived Macrophagesmentioning

confidence: 99%

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Microglia and Monocyte-Derived Macrophages in Stroke

2016

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“…The immune response to stroke differs between males and females. For instance, male mice exhibit an initial increase in infarction characterized by an early and more robust recruitment of CD45 high CD11b+ macrophages into post-ischemic brain relative to females (Banerjee et al 2013; Dotson et al 2015). If the spleen is removed prior to MCAO, sex differences in infarct and activated microglia/macrophages in the brain is lost due to, in part, a decrease of peripheral CD11b+ cells in males only (Dotson et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Sex differences and the role of PPAR alpha in experimental stroke

et al. 2015

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Males and females respond differently to stroke. Moreover, females often experience worse long-term stroke outcomes. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist has been shown to improve stroke outcome and resolve neuroinflammation in male mice. The present study compares the effect of pretreatment with fenofibrate versus vehicle control in male and female mice during experimental stroke. Mice were treated with low-dose fenofibrate 30 minutes before and once a day for three additional days after stroke onset. We observed a reduction in infarct volume in male mice 96 hours post-stroke with low-dose fenofibrate pretreatment that was due to increase of an M2 macrophage phenotype in the brain and an increase in regulatory cells in the periphery. These outcomes were not replicated in females, likely due to the lower PPARα expression in cells and tissues in females vs males. We conclude that PPARα agonist treatment prior to stroke is neuroprotective in males but not females. These findings indicate PPARα as a probable mechanism of sex difference in stroke outcome and support the need for representation of females in stroke therapy research.

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“…Activation of splenocytes after stroke leads to a release of leukocytes into the periphery, followed by infiltration of pathogenic immune cells into the brain and activation of microglial cells, which exacerbate ischemic injury [7–10]. Rodents that are splenectomized prior to middle cerebral artery occlusion (MCAO) exhibit a decrease in infarct volume, associated with reduced inflammatory leukocytes and pro-inflammatory cytokines in the ischemic brain [4, 11]. Additionally, when spleens were irradiated 4 h after MCAO, infarct volume, microglia and infiltrating T cells in the ischemic brain were reduced, presumably due to inhibition of splenocyte efflux [12].…”

Section: Introductionmentioning

confidence: 99%

Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion

Dotson

Chen

Zhu

et al. 2015

Transl. Stroke Res.

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Inflammation and thrombosis are tightly linked, with inflammation contributing to thromboembolism and to stroke outcome. Thromboembolism is a frequent cause of ischemic stroke, yet the most used occlusion mouse models of experimental stroke do not effectively replicate thromboembolism. Our group recently described a novel thromboembolic mouse model of stroke that successfully occludes the middle cerebral artery with high reproducibility. In the current study, we characterize the peripheral and local immune outcomes as well as the ischemic response to immune therapy in a clinically relevant mouse model of thromboembolic stroke. Brain and spleen tissues were harvested 24 hours after thromboembolic stroke and cells immunophenotyped by flow cytometry. We observed a significant increase in neutrophils and early activated T cells in the spleen and an increase in neutrophils and activated monocytes/microglia in the ischemic cortex after thromboembolic stroke. Moreover, as was shown previously for transient MCAO models, treatment of thromboembolic stroke with partial MHC constructs significantly reduced ischemic damage indicating an equivalent effect of this immune-based therapy in the thromboembolic model that better mimics the pathophysiology of human stroke.

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Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke

Cited by 70 publications

References 37 publications

Microglia and Monocyte-Derived Macrophages in Stroke

Microglia and Monocyte-Derived Macrophages in Stroke

Sex differences and the role of PPAR alpha in experimental stroke

Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion

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