Brain-to-cervical lymph node signaling after stroke

Esposito, Elga; Ahn, Bum Ju; Shi, Jingfei; Nakamura, Yoshihiko; Park, Ji Hyun; Mandeville, Emiri T.; Yu, Zhanyang; Chan, Su Jing; Desai, Rakhi; Hayakawa, Ayumi; Ji, Xunming; Lo, Eng H.; Hayakawa, Kazuhide

doi:10.1038/s41467-019-13324-w

Cited by 77 publications

(83 citation statements)

References 67 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are similar to those observed in experimental autoimmune uveitis [ 72 ]. Recently, the pivotal contribution of cervical lymph nodes in particular to post-stroke systemic inflammation and subsequent infarct growth has been described with respect to macrophage-mediated inflammation [ 73 ]. The same study suggested T cells may also be involved.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…However, there are, so far, few data on this in the scientific literature. When simulating focal ischemia in rats, it was shown that blockade of FLT4 (VEGFR3) reduces activation of the lymphatic endothelium, reduces the level of activation of proinflammatory macrophages, and reduces the volume of cerebral infarction [ 27 ]. It has also been demonstrated that VEGFC and VEGFR-3 are involved in the neuroprotective effects of preconditioning in the mouse hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Kinase Inhibition in Ischemic Factor Modeling In Vitro

Митрошина

Loginova

Savyuk

et al. 2021

IJMS

View full text Add to dashboard Cite

The contribution of many neuronal kinases to the adaptation of nerve cells to ischemic damage and their effect on functional neural network activity has not yet been studied. The aim of this work is to study the role of the four kinases belonging to different metabolic cascades (SRC, Ikkb, eEF2K, and FLT4) in the adaptive potential of the neuron-glial network for modeling the key factors of ischemic damage. We carried out a comprehensive study on the effects of kinases blockade on the viability and network functional calcium activity of nerve cells under ischemic factor modeling in vitro. Ischemic factor modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). The most significant neuroprotective effect was shown in the blockade of FLT4 kinase in the simulation of hypoxia. The studies performed revealed the role of FLT4 in the development of functional dysfunction in cerebrovascular accidents and created new opportunities for the study of this enzyme and its blockers in the formation of new therapeutic strategies.

show abstract

“…The anatomy and function of this CNS drainage pathway are just now being defined [15][16][17][18][19][20][21] , and its role in many neurological diseases, including TBI, has not been elucidated. In recently published work, it was shown that these lymphatic vessels drain cerebrospinal fluid (CSF), interstitial fluid (ISF), CNS-derived molecules, and immune cells from the brain and meninges to the deep cervical lymph nodes (dCLN) 15,16,19,22 . Importantly, studies using in vivo magnetic resonance imaging (MRI) techniques have also identified the existence of meningeal lymphatic vessels in both humans and nonhuman primates 23,24 .…”

mentioning

confidence: 99%

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Bolte¹,

Dutta²,

Hurt³

et al. 2020

Nat Commun

186

168

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

show abstract

Brain-to-cervical lymph node signaling after stroke

Cited by 77 publications

References 67 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

Neuroprotective Effect of Kinase Inhibition in Ischemic Factor Modeling In Vitro

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Contact Info

Product

Resources

About