Potential microglia‐based interventions for stroke

Li, Lingzhi; Huang, Yuyou; Yang, Zhenhong; Zhang, Sijia; Han, Ziping; Luo, Yumin

doi:10.1111/cns.13291

Cited by 40 publications

(42 citation statements)

References 116 publications

(198 reference statements)

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“…Recent evidence does suggest a link between the drug and the local inflammatory milieu through upregulation of the anti-inflammatory “M2” microglia phenotype [ 83 ]. It is possible fingolimod enhances modulation to a Treg phenotype via M2 microglia-mediated release of anti-inflammatory cytokines at the infarct site [ 84 ].…”

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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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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“…8 Microglial activation is a neural defense against damage triggered by brain ischemia. 9 Ischemic stroke perturbs endogenous inhibitory signaling and triggers microglial activation 10 that either aggravates ischemic injury or induces repair and regeneration, depending on the different signals received by microglial receptors. 10,11 TREM2 abundance on the microglia cell surface is 300 times higher than on astrocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Clearing of cellular debris by macrophages after brain ischemia is an important mechanism to sustain homeostasis and promote functional recovery 8 . Microglial activation is a neural defense against damage triggered by brain ischemia 9 . Ischemic stroke perturbs endogenous inhibitory signaling and triggers microglial activation 10 that either aggravates ischemic injury or induces repair and regeneration, depending on the different signals received by microglial receptors 10,11 .…”

Section: Introductionmentioning

confidence: 99%

DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke

et al. 2020

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Aims: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secretory neurotrophic factor protein that promotes repair after neuronal injury. The microglia cell surface receptor (triggering receptor expressed on myeloid cells-2; TREM2) regulates the production of pro-and antiinflammatory mediators after stroke. Here, we study MANF and TREM2 expression after middle cerebral artery occlusion (MCAo) and explore if docosahexaenoic acid (DHA) treatment exerts a potentiating effect. Methods: We used 2 hours of the MCAo model in rats and intravenously administered DHA or vehicle at 3 hours after the onset of MCAo. Neurobehavioral assessment was performed on days 1, 3, 7, and 14; MANF and TREM2 expression was measured by immunohistochemistry and Western blotting. Results: MANF was upregulated in neurons and astrocytes on days 1, 7, and 14, and TREM2 was expressed on macrophages in the ischemic penumbra and dentate gyrus (DG) on days 7 and 14. DHA improved neurobehavioral recovery, attenuated infarct size on days 7 and 14, increased MANF and decreased TREM2 expression in ischemic core, penumbra, DG, and enhanced neurogenesis on Day 14. Conclusion: MANF and TREM2 protein abundance is robustly increased after MCAo, and DHA treatment potentiated MANF abundance, decreased TREM2 expression, improved neurobehavioral recovery, reduced infarction, and provided enhanced neuroprotection.

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“…Pro‐inflammatory mechanisms may also contribute to the pathways leading to dementia 38 . Specifically, cerebral atrophy causes microglia and astrocytes to exhibit a dampened cytokine response in stroke‐induced dementia patients 39–41 …”

Section: Pathology Of Chronic Stroke Presenting As Cognitive Impairmentsmentioning

confidence: 99%

“…Both are present with inflammation‐induced cerebral atrophy and secondary neuronal cell death, consequently exacerbating cognitive impairments and physiological damage 33–41,64,84 . Additionally, the role of microglia in both stroke and AD may hint at overlapping pathological mechanisms 40,41,85 . The risk of stroke‐induced dementia may be determined by the presence of prior ischemic injury, vascular comorbidities, WML’s, and genetic predisposition 28 .…”

Section: Potential Translation Of Ad Treatment To Stroke By Targetingmentioning

confidence: 99%

Gut dysbiosis in stroke and its implications on Alzheimer’s disease‐like cognitive dysfunction

et al. 2021

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Various neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut‐brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut‐brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell‐based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut‐microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes.

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Potential microglia‐based interventions for stroke

Cited by 40 publications

References 116 publications

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

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

DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke

Gut dysbiosis in stroke and its implications on Alzheimer’s disease‐like cognitive dysfunction

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