Top

Published in:

Open Access 01-12-2014 | Research

TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain

Authors: Lan-Wan Wang, Ying-Chao Chang, Shyi-Jou Chen, Chien-Hang Tseng, Yi-Fang Tu, Nan-Shih Liao, Chao-Ching Huang, Chien-Jung Ho

Published in: Journal of Neuroinflammation | Issue 1/2014

Abstract

Background

Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood–brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases.

Objective

To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain.

Methods

Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining.

Results

The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI.

Conclusion

TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.

Available only for authorised users

Volpe JJ: Systemic inflammation, oligodendroglial maturation and encephalopathy of prematurity. Ann Neurol. 2011, 70: 525-529. 10.1002/ana.22533.CrossRefPubMed

Leviton A, Paneth N, Reuss ML, Susser M, Allred EN, Dammann O, Kuban K, Marter LJ, Pagano M, Hegyi T, Hiatt M, Sanocka U, Shahrivar F, Abiri M, Disalvo D, Doubilet P, Kairam R, Kazam E, Kirpekar M, Rosenfeld D, Schonfeld S, Share J, Collins M, David Genest D, Debra Heller D, Schwarz SS: Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Pediatr Res. 1999, 46: 566-575. 10.1203/00006450-199911000-00013.CrossRefPubMed

Debillon T, Gras-Leguen C, Vérielle V, Winer N, Caillon J, Rozé JC, Gressens P: Intrauterine infection induces programmed cell death in rabbit periventricular white matter. Pediatr Res. 2000, 47: 736-742. 10.1203/00006450-200006000-00009.CrossRefPubMed

Yanowitz TD, Jordan JA, Gilmour CH, Towbin R, Bowen A, Roberts JM, Brozanski BS: Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res. 2002, 51: 310-316. 10.1203/00006450-200203000-00008.CrossRefPubMed

Wong FY, Silas R, Hew S, Samarasinghe T, Walker AM: Cerebral oxygenation is highly sensitive to blood pressure variability in sick preterm infants. PLoS One. 2012, 7: e43165-10.1371/journal.pone.0043165.PubMedCentralCrossRefPubMed

Kaukola T, Herva R, Perhomma M, Paakko E, Kingsmore S, Vainionpaa L, Hallman M: Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurological outcome in very preterm, extremely low birth weight infants. Pediatr Res. 2006, 59: 478-483. 10.1203/01.pdr.0000182596.66175.ee.CrossRefPubMed

Wang LW, Lin YC, Wang ST, Yeh TF, Huang CC: Hypoxic/ischemic and infectious events have cumulative effects on the risk of cerebral palsy in very-low-birth-weight preterm infants. Neonatology. 2014, 106: 209-215. 10.1159/000362782.CrossRefPubMed

Wang LW, Chang YC, Lin CY, Hong JS, Huang CC: Low-dose lipopolysaccharide selectively sensitizes hypoxia-ischemia-induced white matter injury in the immature brain. Pediatr Res. 2010, 68: 41-47. 10.1203/PDR.0b013e3181df5f6b.PubMedCentralCrossRefPubMed

Wang LW, Tu YF, Huang CC, Ho CJ: JNK signaling is the shared pathway linking neuro-inflammation, blood–brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain. J Neuroinflammation. 2012, 9: 175-10.1186/1742-2094-9-175.PubMedCentralCrossRefPubMed

10.

del Zoppo GJ: Stroke and neurovascular protection. N Engl J Med. 2006, 354: 553-555. 10.1056/NEJMp058312.CrossRefPubMed

11.

Tu YF, Tsai YS, Wang LW, Wu HC, Huang CC, Ho CJ: Overweight worsens apoptosis, neuroinflammation and blood–brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation. J Neuroinflammation. 2011, 8: 40-10.1186/1742-2094-8-40.PubMedCentralCrossRefPubMed

12.

Tu YF, Lu PJ, Huang CC: Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke. 2012, 43: 491-498. 10.1161/STROKEAHA.111.629931.CrossRefPubMed

13.

Back SA, Luo NL, Borenstein NS, Levin JM, Volpe JJ, Kinney HC: Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001, 21: 1302-1312.PubMed

14.

Chew LJ, Takanohashi A, Bell M: Microglia and inflammation: impact on developmental brain injuries. Ment Retard Dev Disabil Res Rev. 2006, 12: 105-112. 10.1002/mrdd.20102.CrossRefPubMed

15.

Dammann O, Durums S, Leviton A: Do white cells matter in white matter damage?. Trends Neurosci. 2001, 24: 320-324. 10.1016/S0166-2236(00)01811-7.CrossRefPubMed

16.

Manning AM, Davis RJ: Target JNK for therapeutic benefit: from Junk to gold?. Nat Rev Drug Discov. 2003, 2: 554-565. 10.1038/nrd1132.CrossRefPubMed

17.

Kadhim H, Tabarki B, Verellen G, De Prez C, Rona AM, Sebire G: Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurology. 2001, 56: 1278-1284. 10.1212/WNL.56.10.1278.CrossRefPubMed

18.

Kadhim H, Khalifa M, Deltenre P, Casimir G, Sebire G: Molecular mechanisms of cell death in periventricular leukomalacia. Neurology. 2006, 67: 293-299. 10.1212/01.wnl.0000224754.63593.c4.CrossRefPubMed

19.

Varfolomeev EE, Ashkenazi A: Tumor necrosis factor: an apoptosis JuNKie?. Cell. 2004, 116: 491-497. 10.1016/S0092-8674(04)00166-7.CrossRefPubMed

20.

Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U: Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci. 2002, 22: 1-7.

21.

Pan W, Kastin A: Tumor necrosis factor and stroke: role of the blood–brain barrier. Prog Neurobiol. 2007, 83: 363-374. 10.1016/j.pneurobio.2007.07.008.PubMedCentralCrossRefPubMed

22.

Works MG, Koenig JB, Sapolsky RM: Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. J Cereb Blood Flow Metab. 2013, 33: 1376-1385. 10.1038/jcbfm.2013.100.PubMedCentralCrossRefPubMed

23.

Nijboer CH, van der Kooij MA, van Bel F, Ohl F, Heijnen CJ, Kavelaars A: Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury. Brain Behav Immun. 2010, 24: 812-821. 10.1016/j.bbi.2009.09.008.CrossRefPubMed

24.

Rice JE, Vannucci RC, Brierley JB: The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981, 9: 131-141. 10.1002/ana.410090206.CrossRefPubMed

25.

Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, Hagberg H, Blomgren K: The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ. 2005, 12: 162-176. 10.1038/sj.cdd.4401545.CrossRefPubMed

26.

McCoy MK, Tansey MG: TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008, 5: 45-10.1186/1742-2094-5-45.PubMedCentralCrossRefPubMed

27.

Aden U, Favrais G, Plaisant F, Winerdal M, Felderhoff-Mueser U, Lampa J, Lelievre V, Gressens P: Systemic inflammation sensitizes the neonatal brain to excito-toxicity through a pro-/anti-inflammatory imbalance: key role of TNF-α pathway and protection by etanercept. Brain Behav Immun. 2010, 24: 747-758. 10.1016/j.bbi.2009.10.010.CrossRefPubMed

28.

Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA: AS601245 (1,3-benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuro-protective properties. J Pharmacol Exp Ther. 2004, 310: 25-32. 10.1124/jpet.103.064246.CrossRefPubMed

29.

Paxinos G, Watson C: The Mouse Brain in Stereotaxic Coordinates. 2001, Academic, New York

30.

Svedin P, Hagberg H, Savman K, Zhu C, Mallard C: Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci. 2007, 27: 1511-1518. 10.1523/JNEUROSCI.4391-06.2007.CrossRefPubMed

31.

Hagberg H, Gressens P, Mallard C: Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012, 71: 444-457. 10.1002/ana.22620.CrossRefPubMed

32.

Tam SJ, Watts RJ: Connecting vascular and nervous system development: angiogenesis and the blood–brain barrier. Annu Rev Neurosci. 2010, 33: 379-408. 10.1146/annurev-neuro-060909-152829.CrossRefPubMed

33.

Quaegebeur A, Lange C, Carmeliet P: The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron. 2011, 71: 406-424. 10.1016/j.neuron.2011.07.013.CrossRefPubMed

34.

Hsu YC, Chang YC, Lin YC, Sze CI, Huang CC, Ho CJ: Cerebral micro-vascular damage occurs early after hypoxia-ischemia via nNOS activation in neonatal brain. J Cereb Blood Flow Metab. 2014, 34: 668-676. 10.1038/jcbfm.2013.244.PubMedCentralCrossRefPubMed

35.

Favrais G, van de Looij Y, Fleiss B, Ramanantsoa N, Bonnin P, Stoltenburg-Didinger G, Lacaud A, Saliba E, Dammann O, Gallego J, Sizonenko S, Hagberg H, Vincent L, Gressens P: Systemic inflammation disrupts the developmental program of white matter. Ann Neurol. 2011, 70: 550-565. 10.1002/ana.22489.CrossRefPubMed

36.

Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E: Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr Res. 2006, 59: 428-433. 10.1203/01.pdr.0000199905.08848.55.CrossRefPubMed

37.

Eklind S, Hagberg H, Wang X, Savman K, Leverin AL, Hedtjarn M, Mallard C: Effect of lipopolysaccharide on global gene expression in the immature rat brain. Pediatr Res. 2006, 60: 161-168. 10.1203/01.pdr.0000228323.32445.7d.CrossRefPubMed

38.

Kendall GS, Hirstova M, Horn S, Dafou D, Acosta-Saltos A, Almolda B, Zbarsky V, Rumajogee P, Heuer H, Castellano B, Pfeffer K, Nedospasov SA, Peebles DM, Raivich G: TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult. Lab Invest. 2011, 91: 328-341. 10.1038/labinvest.2010.192.CrossRefPubMed

39.

Markus T, Cronberg T, Cilio C, Pronk C, Wieloch T, Ley D: Tumor necrosis factor receptor-1 is essential for LPS-induced sensitization and tolerance to oxygen-glucose deprivation in murine neonatal organo-typic hippocampal slices. J Cereb Blood Flow Metab. 2009, 29: 73-86. 10.1038/jcbfm.2008.90.CrossRefPubMed

40.

Kichev A, Rousset C, Baburamani AA, Levison SW, Wood TL, Gressens P, Thornton C, Hagberg H: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation. J Biol Chem. 2014, 289: 9430-9439. 10.1074/jbc.M113.512350.PubMedCentralCrossRefPubMed

41.

Kuno R, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A: Autocrine activation of microglia by tumor necrosis factor-α. J Neuroimmunol. 2005, 162: 89-96. 10.1016/j.jneuroim.2005.01.015.CrossRefPubMed

42.

Rosenberg GA: Matrix metalloproteinases in neuroinflammation. Glia. 2002, 39: 279-291. 10.1002/glia.10108.CrossRefPubMed

43.

Yatsusshige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH: Role of c-Jun N-terminal Kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res. 2007, 85: 1436-1448. 10.1002/jnr.21281.CrossRef

44.

Lucas R, Garcia I, Donati YRA, Hribar M, Mandriota SJ, Giroud C, Buurman WA, Fransen L, Suter PM, Nunez G, Pepper MS, Grau GE: Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells. Eur J Immunol. 1998, 28: 3577-3586. 10.1002/(SICI)1521-4141(199811)28:11<3577::AID-IMMU3577>3.0.CO;2-#.CrossRefPubMed

45.

Karashi H, Michelsen KS, Arditi M: Lipopolysaccharide-induced apoptosis in transformed bovine brain endothelial cells and human dermal microvessel endothelial cells: the role of JNK. J Immunol. 2009, 182: 7280-7286. 10.4049/jimmunol.0801376.CrossRef

46.

Hosomi N, Ban CR, Naya T, Takahashi T, Guo P, Song XY, Kohno M: Tumor necrosis factor-α neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2005, 25: 959-967. 10.1038/sj.jcbfm.9600086.CrossRefPubMed

47.

D’Mello C, Le T, Swain MG: Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor-α signaling during peripheral organ inflammation. J Neurosci. 2009, 29: 2089-2102. 10.1523/JNEUROSCI.3567-08.2009.CrossRefPubMed

48.

Kadhim H, Tabarki B, De Prez C, Sebire G: Cytokine immunoreactivity in cortical and subcortical neurons in periventricular leukomalacia: are cytokines implicated in neuronal dysfunction in cerebral palsy?. Acta Neuropathol. 2003, 105: 209-216.PubMed

49.

Deng YY, Lu J, Sivakumar V, Ling EA, Kaur C: Amoeboid microglia in the peri-ventricular white matter induce oligodendrocyte damage through expression of pro-inflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol. 2008, 18: 387-400. 10.1111/j.1750-3639.2008.00138.x.CrossRefPubMed

50.

Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA: Tumor necrosis factor-α mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present. J Neurosci. 2008, 28: 5321-5330. 10.1523/JNEUROSCI.3995-07.2008.PubMedCentralCrossRefPubMed

51.

Badiola N, Malagelada C, Llecha N, Hidalgo J, Comella JX, Sabria J, Rodriguez-Alvarez J: Activation of caspase-8 by tumor necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol Dis. 2009, 35: 438-447. 10.1016/j.nbd.2009.06.005.CrossRefPubMed

52.

Pirianov G, Jesurasa A, Mehmet H: Developmentally regulated changes in c-Jun N-terminal kinase signaling determine the apoptotic response of oligodendrocyte lineage cells. Cell Death Differ. 2006, 13: 531-533. 10.1038/sj.cdd.4401805.CrossRefPubMed

Title: TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain
Authors: Lan-Wan Wang
Ying-Chao Chang
Shyi-Jou Chen
Chien-Hang Tseng
Yi-Fang Tu
Nan-Shih Liao
Chao-Ching Huang
Chien-Jung Ho
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-014-0215-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain

Abstract

Background

Objective

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2014

Critical role of inflammatory cytokines in impairing biochemical processes for learning and memory after surgery in rats

Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice

Knockout of CXCR5 increases the population of immature neural cells and decreases proliferation in the hippocampal dentate gyrus

Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring

No effect of ablation of surfactant protein-D on acute cerebral infarction in mice

Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies