Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice

Ahnstedt, Hilda; Patrizz, Anthony; Chauhan, Anjali; Roy-O’Reilly, Meaghan; Furr, J. Weldon; Spychala, Monica; d’Aigle, John; Blixt, Frank W; Zhu, Liang; Alegria, Javiera Bravo; McCullough, Louise D.

doi:10.1016/j.bbi.2020.02.001

Cited by 65 publications

(51 citation statements)

References 76 publications

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“…16,18,19 The increase of brain Tregs was significantly higher in aged male mice than in females at 15 days after tMCAO, indicating that the immune response of brain T cells may be time-specific and gender-specific. 20 In contrast to these findings, Kleinschnitz et al found a marked increase of Foxp3 + Tregs in the brain within 24 hours after tMCAO, but predominantly in the cerebral vasculature. 21 Moreover, on day 3 after permanent middle cerebral artery occlusion (pMCAO), Tregs on the ischemic hemisphere accounted for about 20% of CD4 + T cells, which may cause more severe neuroinflammatory reaction.…”

Section: Changes In the Number Of Tregs In The Brain After Ischemic Strokementioning

confidence: 87%

“…Tregs may proliferate on the ischemic hemisphere side 7 days after tMCAO, indicating a possible kinetic delay in the adaptive immune response 16,18,19 . The increase of brain Tregs was significantly higher in aged male mice than in females at 15 days after tMCAO, indicating that the immune response of brain T cells may be time‐specific and gender‐specific 20 . In contrast to these findings, Kleinschnitz et al found a marked increase of Foxp3 + Tregs in the brain within 24 hours after tMCAO, but predominantly in the cerebral vasculature 21 .…”

Section: Dynamic Changes Of Tregs In Various Stages Of Experimental Ischemic Strokementioning

confidence: 99%

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Regulatory T cells in ischemic stroke

Wang

et al. 2021

CNS Neurosci Ther

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The pathophysiological mechanisms of neuroinflammation, angiogenesis, and neuroplasticity are currently the hotspots of researches in ischemic stroke. Regulatory T cells (Tregs), a subset of T cells that control inflammatory and immune responses in the body, are closely related to the pathogenesis of ischemic stroke. They participate in the inflammatory response and neuroplasticity process of ischemic stroke by various mechanisms, such as secretion of anti‐inflammatory factors, inhibition of pro‐inflammatory factors, induction of cell lysis, production of the factors that promote neural regeneration, and modulation of microglial and macrophage polarization. However, it remains unclear whether Tregs play a beneficial or deleterious role in ischemic stroke and the effect of Tregs in different stages of ischemic stroke. Here, we discuss the dynamic changes of Tregs at various stages of experimental and clinical stroke, the potential mechanisms under Tregs in regulating stroke and the preclinical studies of Tregs‐related treatments, in order to provide a reference for clinical treatment.

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Section: Changes In the Number Of Tregs In The Brain After Ischemic Strokementioning

confidence: 87%

Section: Dynamic Changes Of Tregs In Various Stages Of Experimental Ischemic Strokementioning

confidence: 99%

Regulatory T cells in ischemic stroke

Wang

et al. 2021

CNS Neurosci Ther

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“…This study shows for the first time that fingolimod also increases peripheral Treg frequency post-ischaemia and enhances FoxP3+ cells in the infarcted brain. These effects were observed in young mice but also notably in aged and ApoE −/− mice, two common stroke comorbidities with known alterations in T cell function [ 70 , 89 ]. The fingolimod dose and treatment schedule needed to maximize these effects were also investigated.…”

Section: Discussionmentioning

confidence: 99%

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

Malone

Díaz

Shearer

et al. 2021

J Neuroinflammation

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Background The role of the immune system in stroke is well-recognised. Fingolimod, an immunomodulatory agent licensed for the management of relapsing-remitting multiple sclerosis, has been shown to provide benefit in rodent models of stroke. Its mechanism of action, however, remains unclear. We hypothesised fingolimod increases the number and/or function of regulatory T cells (Treg), a lymphocyte population which promotes stroke recovery. The primary aim of this study was to rigorously investigate the effect of fingolimod on Tregs in a mouse model of brain ischaemia. The effect of fingolimod in mice with common stroke-related comorbidities (ageing and hypercholesteremia) was also investigated. Methods Young (15–17 weeks), aged C57BL/6 mice (72–73 weeks), and ApoE−/− mice fed a high-fat diet (20–21 weeks) underwent permanent electrocoagulation of the left middle cerebral artery. Mice received either saline or fingolimod (0.5 mg/kg or 1 mg/kg) at 2, 24, and 48 h post-ischaemia via intraperitoneal injection. Another cohort of young mice (8–9, 17–19 weeks) received short-term (5 days) or long-term (10 days) fingolimod (0.5 mg/kg) treatment. Flow cytometry was used to quantify Tregs in blood, spleen, and lymph nodes. Immunohistochemistry was used to quantify FoxP3+ cell infiltration into the ischaemic brain. Results Fingolimod significantly increased the frequency of Tregs within the CD4+ T cell population in blood and spleen post-ischaemia in all three mouse cohorts compared to untreated ischemic mice. The highest splenic Treg frequency in fingolimod-treated mice was observed in ApoE−/− mice (9.32 ± 1.73% vs. 7.8 ± 3.01% in young, 6.09 ± 1.64% in aged mice). The highest circulating Treg frequency was also noted in ApoE−/− mice (8.39 ± 3.26% vs. 5.43 ± 2.74% in young, 4.56 ± 1.60% in aged mice). Fingolimod significantly increased the number of FoxP3+ cells in the infarct core of all mice. The most pronounced effects were seen when mice were treated for 10 days post-ischaemia. Conclusions Fingolimod increases Treg frequency in spleen and blood post-ischaemia and enhances the number of FoxP3+ cells in the ischaemic brain. The effect of fingolimod on this regulatory cell population may underlie its neuroprotective activity and could be exploited as part of future stroke therapy.

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“…While several recent studies have shown that gut dysbiosis is associated with common risk factors for stroke, such as age (Spychala et al, 2018), obesity (Ley et al, 2006) and metabolic disease (Sato et al, 2014), only one previous study has reported on sex specific gut disruption in association with stroke injury. While aged males and females typically have worse stroke outcomes than young animals, this study showed that aged males fare worse than aged females after stroke, and display persistent changes in gut dysbiosis as well as more prominent T-cell responses in the brain (Ahnstedt et al, 2020).…”

Section: Introductionmentioning

confidence: 61%

“…Our data also show that the gut is an early responder to stroke. Within minutes of MCAo, gut permeability is altered as measured by extravasation of oral-gavage dextrans, and a new report indicates that a low grade permeability (4kD) can be detected 3d post MCAo (Ahnstedt et al, 2020). Disruption of the epithelial barrier likely results in part from stroke-induced activation of the vagus nerve as well as by inflammatory signals from the brain which act on the gut epithelium to increase gut permeability and gut motility (reviewed in (Arya and Hu, 2018).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

El-Hakim

Mani

Eldouh

et al. 2020

Preprint

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Background: Sex differences in experimental stroke are well documented, such that adult males show worse outcomes compared to adult females, including greater infarct volume, increased stroke-induced mortality and more severe sensory-motor impairment. Based on recent evidence that gut dysbiosis may be an early response to stroke, the present study tested the hypothesis that in the acute phase, stroke will result in greater permeability of the gut blood barrier and gut dysbiosis in males as compared to females. Method: Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were conducted pre and 2d after MCAo. Fecal samples were analyzed for 16s sequencing and short chain fatty acids (SCFAs). Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Results: We confirmed stroke-induced sex differences, including greater mortality and sensory motor deficit in males as compared to age-matched female rats. Remarkably, fecal 16s sequencing showed greater bacterial diversity in females at baseline (prior to stroke) while 2 days after stroke, these measures were similar between the sexes. In contrast, fecal levels of short chain fatty acids (SCFAs) which are usually beneficial, were higher in males. MCAo-induced gut permeability was much worse in males as compared to females, as indicated by histological analysis, biochemical markers in serum, and serum measurement of fluorescent-labeled dextrans following oral gavage. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Predictive modeling indicated that markers of gut permeability were associated with stroke-induced sensory-motor impairment. Conclusions: Poor stroke outcomes in adult males is mirrored by increased gut permeability in this group. Additionally, these data suggest that constitutive sex differences in the diversity and richness of gut microbial communities may predispose better functional outcomes after stroke in females, and support the idea that preventative modification of the gut microbiome may reduce the risk for stroke in vulnerable populations such as the elderly or those with co-morbid conditions.

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Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice

Cited by 65 publications

References 76 publications

Regulatory T cells in ischemic stroke

Regulatory T cells in ischemic stroke

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

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