Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Septicemia | Research

TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation

Authors: Wan-Yu Huang, Yen-Ling Lai, Ko-Hung Liu, Shankung Lin, Hsuan-Ying Chen, Chih-Hung Liang, Hung-Ming Wu, Kuei-Sen Hsu

Published in: Journal of Neuroinflammation | Issue 1/2022

Login to get access

Abstract

Background

Systemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).

Methods

Lipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.

Results

Some noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.

Conclusions

The findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.
Appendix
Available only for authorised users
Literature
1.
Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T. Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013;3:15.PubMedPubMedCentral
2.
Idro R, Gwer S, Kahindi M, Gatakaa H, Kazungu T, Ndiritu M, Maitland K, Neville BG, Kager PA, Newton CR. The incidence, aetiology and outcome of acute seizures in children admitted to a rural Kenyan district hospital. BMC Pediatr. 2008;8:5.PubMedPubMedCentral
3.
4.
Riazi K, Galic MA, Pittman QJ. Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res. 2010;89:34–42.PubMed
5.
Cerri C, Genovesi S, Allegra M, Pistillo F, Puntener U, Guglielmotti A, Perry VH, Bozzi Y, Caleo M. The chemokine CCL2 mediates the seizure-enhancing effects of systemic inflammation. J Neurosci. 2016;36:3777–88.PubMedPubMedCentral
6.
Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ, Kalynchuk LE, Teskey GC, Pittman QJ. Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci. 2008;28:6904–13.PubMedPubMedCentral
7.
Huang WY, Lin S, Chen HY, Chen YP, Chen TY, Hsu KS, Wu HM. NADPH oxidases as potential pharmacological targets against increased seizure susceptibility after systemic inflammation. J Neuroinflammation. 2018;15:140.PubMedPubMedCentral
8.
Harre EM, Galic MA, Mouihate A, Noorbakhsh F, Pittman QJ. Neonatal inflammation produces selective behavioural deficits and alters N-methyl-D-aspartate receptor subunit mRNA in the adult rat brain. Eur J Neurosci. 2008;27:644–53.PubMedPubMedCentral
9.
Kovacs R, Heinemann U, Steinhauser C. Mechanisms underlying blood-brain barrier dysfunction in brain pathology and epileptogenesis: role of astroglia. Epilepsia. 2012;53(Suppl 6):53–9.PubMed
10.
Baruah J, Vasudevan A, Kohling R. Vascular integrity and signaling determining brain development, network excitability, and epileptogenesis. Front Physiol. 2019;10:1583.PubMed
11.
Lecuyer MA, Kebir H, Prat A. Glial influences on BBB functions and molecular players in immune cell trafficking. Biochim Biophys Acta. 2016;1862:472–82.PubMed
12.
Elwood E, Lim Z, Naveed H, Galea I. The effect of systemic inflammation on human brain barrier function. Brain Behav Immun. 2017;62:35–40.PubMedPubMedCentral
13.
Rochfort KD, Cummins PM. The blood–brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans. 2015;43:702–6.PubMed
14.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1–12.PubMed
15.
Ohno Y, Tokudome K, Kunisawa N, Iha HA, Kinboshi M, Mukai T, Serikawa T, Shimizu S. Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy. Ther Targets Neurol Dis. 2015;2: e476.
16.
Olsen ML, Sontheimer H. Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem. 2008;107:589–601.PubMedPubMedCentral
17.
Newton K, Manning G. Necroptosis and inflammation. Annu Rev Biochem. 2016;85:743–63.PubMed
18.
19.
20.
Chen AQ, Fang Z, Chen XL, Yang S, Zhou YF, Mao L, Xia YP, Jin HJ, Li YN, You MF, et al. Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis. 2019;10:487.PubMedPubMedCentral
21.
Zille M, Ikhsan M, Jiang Y, Lampe J, Wenzel J, Schwaninger M. The impact of endothelial cell death in the brain and its role after stroke: a systematic review. Cell Stress. 2019;3:330–47.PubMedPubMedCentral
22.
Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK, Mele T. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 2014;7:233.PubMedPubMedCentral
23.
Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci. 1996;16:1337–45.PubMedPubMedCentral
24.
25.
Huang WY, Liu KH, Lin S, Chen TY, Tseng CY, Chen HY, Wu HM, Hsu KS. NADPH oxidase 2 as a potential therapeutic target for protection against cognitive deficits following systemic inflammation in mice. Brain Behav Immun. 2020;84:242–52.PubMed
26.
Tao K, Cai Q, Zhang X, Zhu L, Liu Z, Li F, Wang Q, Liu L, Feng D. Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1. Ann Transl Med. 2020;8:691.PubMedPubMedCentral
27.
Chen HY, Cheng FC, Pan HC, Hsu JC, Wang MF. Magnesium enhances exercise performance via increasing glucose availability in the blood, muscle, and brain during exercise. PLoS ONE. 2014;9: e85486.PubMedPubMedCentral
28.
Mao XY, Zhou HH, Jin WL. Redox-related neuronal death and crosstalk as drug targets: focus on epilepsy. Front Neurosci. 2019;13:512.PubMedPubMedCentral
29.
Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 2013;36:174–84.PubMed
30.
Blaser H, Dostert C, Mak TW, Brenner D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 2016;26:249–61.PubMed
31.
Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K, Kubo T, Kurachi Y. An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol. 2001;281:C922–31.PubMed
32.
Kucheryavykh YV, Kucheryavykh LY, Nichols CG, Maldonado HM, Baksi K, Reichenbach A, Skatchkov SN, Eaton MJ. Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes. Glia. 2007;55:274–81.PubMed
33.
Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD. Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci. 2007;27:11354–65.PubMedPubMedCentral
34.
Ohno Y. Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders. Neural Regen Res. 2018;13:651–2.PubMedPubMedCentral
35.
Inyushin M, Kucheryavykh LY, Kucheryavykh YV, Nichols CG, Buono RJ, Ferraro TN, Skatchkov SN, Eaton MJ. Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice. Epilepsia. 2010;51:1707–13.PubMedPubMedCentral
36.
Zurolo E, de Groot M, Iyer A, Anink J, van Vliet EA, Heimans JJ, Reijneveld JC, Gorter JA, Aronica E. Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 beta. J Neuroinflammation. 2012;9:280.PubMedPubMedCentral
37.
Nwaobi SE, Cuddapah VA, Patterson KC, Randolph AC, Olsen ML. The role of glial-specific Kir4.1 in normal and pathological states of the CNS. Acta Neuropathol. 2016;132:1–21.PubMedPubMedCentral
38.
van Vliet EA, da Costa AS, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain. 2007;130:521–34.PubMed
39.
Marchi N, Tierney W, Alexopoulos AV, Puvenna V, Granata T, Janigro D. The etiological role of blood-brain barrier dysfunction in seizure disorders. Cardiovasc Psychiatry Neurol. 2011;2011: 482415.PubMedPubMedCentral
40.
Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N, Meabon JS, Wing EE, Morofuji Y, Cook DG, Reed MJ. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation. 2015;12:223.PubMedPubMedCentral
41.
Li JH, Pober JS. The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human endothelial injury. J Immunol. 2005;175:1858–66.PubMed
42.
Zelic M, Roderick JE, O’Donnell JA, Lehman J, Lim SE, Janardhan HP, Trivedi CM, Pasparakis M, Kelliher MA. RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J Clin Invest. 2018;128:2064–75.PubMedPubMedCentral
43.
Clark PR, Kim RK, Pober JS, Kluger MS. Tumor necrosis factor disrupts claudin-5 endothelial tight junction barriers in two distinct NF-kappaB-dependent phases. PLoS ONE. 2015;10: e0120075.PubMedPubMedCentral
44.
Elahy M, Jackaman C, Mamo JC, Lam V, Dhaliwal SS, Giles C, Nelson D, Takechi R. Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immun Ageing. 2015;12:2.PubMedPubMedCentral
45.
Moriwaki K, Chan FK. The inflammatory signal adaptor RIPK3: functions beyond necroptosis. Int Rev Cell Mol Biol. 2017;328:253–75.PubMed
46.
Erickson MA, Banks WA. Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun. 2011;25:1637–48.PubMedPubMedCentral
47.
Lehtimaki KA, Peltola J, Koskikallio E, Keranen T, Honkaniemi J. Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res. 2003;110:253–60.PubMed
48.
Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open. 2018;3:133–42.PubMedPubMedCentral
49.
Cai Q, Gan J, Luo R, Qu Y, Li S, Wan C, Mu D. The role of necroptosis in status epilepticus-induced brain injury in juvenile rats. Epilepsy Behav. 2017;75:134–42.PubMed
50.
Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, Qi D, Lin C, Tong R, Wang Y. RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med. 2019;44:771–86.PubMedPubMedCentral
51.
52.
Fauster A, Rebsamen M, Huber KV, Bigenzahn JW, Stukalov A, Lardeau CH, Scorzoni S, Bruckner M, Gridling M, Parapatics K, et al. A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis. Cell Death Dis. 2015;6: e1767.PubMedPubMedCentral
Metadata
Title
TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation
Authors
Wan-Yu Huang
Yen-Ling Lai
Ko-Hung Liu
Shankung Lin
Hsuan-Ying Chen
Chih-Hung Liang
Hung-Ming Wu
Kuei-Sen Hsu
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02406-0

Other articles of this Issue 1/2022

Journal of Neuroinflammation 1/2022 Go to the issue

Research

Thrombin acts as inducer of proinflammatory macrophage migration inhibitory factor in astrocytes following rat spinal cord injury

Research

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis

Research

Transient neuroinflammation following surgery contributes to long-lasting cognitive decline in elderly rats via dysfunction of synaptic NMDA receptor

Research

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Research

Evaluation of neuroprotective and immunomodulatory properties of mesenchymal stem cells in an ex vivo retinal explant model

Research

Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimer’s disease