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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway

Authors: Yiting Zhang, Yan Ding, Tai Lu, Yixin Zhang, Ningbo Xu, Devin W. McBride, Jiping Tang, John H. Zhang

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury.

Methods

The current study investigated the mechanistic role of biliverdin reductase-A (BLVRA) in the splenic response and brain damage in neonates following a collagenase GMH model. Neurological outcomes and splenic weights were assessed. Neutrophil production and infiltration were quantitated in the spleen and brain, respectively. Western blot was performed in both splenic and brain tissues to measure protein levels of toll-like receptor 4 and proinflammatory cytokines.

Results

BLVRA treatment alleviated GMH-induced developmental delay and attenuated splenic atrophy at 1 and 3 days after GMH. Quantification analysis showed that spleen-stored peripheral immune cells mobilized into circulation and infiltrated in the brain following GMH, which was abrogated by BLVRA administration, resulting in reduced splenic inflammatory response. Furthermore, we showed that regulation of eNOS/NO signaling by BLVRA stimulation blunted toll-like receptor-4 (TLR4) signal. The eNOS-generated NO, in part, translocated BLVRA into the nucleus, where BLVRA inhibited TLR4 expression.

Conclusion

We revealed a BLVRA-dependent signaling pathway in modulating the splenic inflammation in response to GMH via the eNOS/NO/TLR4 pathway.
Literature
1.
2.
3.
Kadri H, Mawla AA, Kazah J. The incidence, timing, and predisposing factors of germinal matrix and intraventricular hemorrhage (GMH/IVH) in preterm neonates. Childs Nerv Syst. 2006;22:1086–90.CrossRefPubMed
4.
Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clin Perinatol. 2014;41:47–67.CrossRefPubMed
5.
Pennypacker KR, Offner H. The role of the spleen in ischemic stroke. J Cereb Blood Flow Metab. 2015;35:186–7.CrossRefPubMed
6.
Ajmo CT Jr, Collier LA, Leonardo CC, Hall AA, Green SM, Womble TA, Cuevas J, Willing AE, Pennypacker KR. Blockade of adrenoreceptors inhibits the splenic response to stroke. Exp Neurol. 2009;218:47–55.CrossRefPubMedPubMedCentral
7.
Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654–65.CrossRefPubMed
8.
Planas AM, Gomez-Choco M, Urra X, Gorina R, Caballero M, Chamorro A. Brain-derived antigens in lymphoid tissue of patients with acute stroke. J Immunol. 2012;188:2156–63.CrossRefPubMed
9.
Seifert HA, Hall AA, Chapman CB, Collier LA, Willing AE, Pennypacker KR. A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J NeuroImmune Pharmacol. 2012;7:1017–24.CrossRefPubMedPubMedCentral
10.
Ostrowski RP, Schulte RW, Nie Y, Ling T, Lee T, Manaenko A, Gridley DS, Zhang JH. Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model. Transl Stroke Res. 2012;3:473–81.CrossRefPubMedPubMedCentral
11.
Fathali N, Ostrowski RP, Hasegawa Y, Lekic T, Tang J, Zhang JH. Splenic immune cells in experimental neonatal hypoxia-ischemia. Transl Stroke Res. 2013;4:208–19.CrossRefPubMed
12.
Ajmo CT Jr, Vernon DO, Collier L, Hall AA, Garbuzova-Davis S, Willing A, Pennypacker KR. The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res. 2008;86:2227–34.CrossRefPubMedPubMedCentral
13.
Jansen T, Hortmann M, Oelze M, Opitz B, Steven S, Schell R, Knorr M, Karbach S, Schuhmacher S, Wenzel P, et al. Conversion of biliverdin to bilirubin by biliverdin reductase contributes to endothelial cell protection by heme oxygenase-1-evidence for direct and indirect antioxidant actions of bilirubin. J Mol Cell Cardiol. 2010;49:186–95.CrossRefPubMed
14.
Dore S, Takahashi M, Ferris CD, Zakhary R, Hester LD, Guastella D, Snyder SH. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci U S A. 1999;96:2445–50.CrossRefPubMedPubMedCentral
15.
Dore S, Sampei K, Goto S, Alkayed NJ, Guastella D, Blackshaw S, Gallagher M, Traystman RJ, Hurn PD, Koehler RC, Snyder SH. Heme oxygenase-2 is neuroprotective in cerebral ischemia. Mol Med. 1999;5:656–63.PubMed
16.
Dore S, Goto S, Sampei K, Blackshaw S, Hester LD, Ingi T, Sawa A, Traystman RJ, Koehler RC, Snyder SH. Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia. Neuroscience. 2000;99:587–92.CrossRefPubMed
17.
Barone E, Di Domenico F, Cassano T, Arena A, Tramutola A, Lavecchia MA, Coccia R, Butterfield DA, Perluigi M. Impairment of biliverdin reductase-a promotes brain insulin resistance in Alzheimer disease: a new paradigm. Free Radic Biol Med. 2016;91:127–42.CrossRefPubMed
18.
Ferenbach DA, Kluth DC, Hughes J. Hemeoxygenase-1 and renal ischaemia-reperfusion injury. Nephron Exp Nephrol. 2010;115:e33–7.CrossRefPubMed
19.
Ferenbach DA, Ramdas V, Spencer N, Marson L, Anegon I, Hughes J, Kluth DC. Macrophages expressing heme oxygenase-1 improve renal function in ischemia/reperfusion injury. Mol Ther. 2010;18:1706–13.CrossRefPubMedPubMedCentral
20.
Hu Z, Pei G, Wang P, Yang J, Zhu F, Guo Y, Wang M, Yao Y, Zeng R, Liao W, Xu G. Biliverdin Reductase A (BVRA) mediates macrophage expression of Interleukin-10 in injured kidney. Int J Mol Sci. 2015;16:22621–35.CrossRefPubMedPubMedCentral
21.
Wegiel B, Gallo D, Csizmadia E, Roger T, Kaczmarek E, Harris C, Zuckerbraun BS, Otterbein LE. Biliverdin inhibits toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase. Proc Natl Acad Sci U S A. 2011;108:18849–54.CrossRefPubMedPubMedCentral
22.
Lekic T, Manaenko A, Rolland W, Krafft PR, Peters R, Hartman RE, Altay O, Tang J, Zhang JH. Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus. Exp Neurol. 2012;236:69–78.CrossRefPubMedPubMedCentral
23.
Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, Zhang JH. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab. 2004;24:1133–45.CrossRefPubMed
24.
25.
Kumar V, Sharma A. Neutrophils: Cinderella of innate immune system. Int Immunopharmacol. 2010;10:1325–34.CrossRefPubMed
26.
Chu H, Zhou J, Wong BH, Li C, Cheng ZS, Lin X, Poon VK, Sun T, Lau CC, Chan JF, et al. Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology. 2014;454-455:197–205.CrossRefPubMed
27.
Seki H, Ueno Y, Taga K, Matsuda A, Miyawaki T, Taniguchi N. Mode of in vitro augmentation of natural killer cell activity by recombinant human interleukin 2: a comparative study of Leu-11+ and Leu-11- cell populations in cord blood and adult peripheral blood. J Immunol. 1985;135:2351–6.PubMed
28.
Cook JL, Ikle DN, Routes BA. Natural killer cell ontogeny in the athymic rat. Relationship between functional maturation and acquired resistance to E1A oncogene-expressing sarcoma cells. J Immunol. 1995;155:5512–8.PubMed
29.
Kim E, Yang J, Beltran CD, Cho S. Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab. 2014;34:1411–9.CrossRefPubMedPubMedCentral
30.
Schwulst SJ, Trahanas DM, Saber R, Perlman H. Traumatic brain injury-induced alterations in peripheral immunity. J Trauma Acute Care Surg. 2013;75:780–8.CrossRefPubMedPubMedCentral
31.
Offner H, Vandenbark AA, Hurn PD. Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience. 2009;158:1098–111.CrossRefPubMed
32.
Georgiadis P, Xu H, Chua C, Hu F, Collins L, Huynh C, Lagamma EF, Ballabh P. Characterization of acute brain injuries and neurobehavioral profiles in a rabbit model of germinal matrix hemorrhage. Stroke. 2008;39:3378–88.CrossRefPubMed
33.
Zhang Y, Ding Y, Lu T, Zhang Y, Xu N, Yu L, McBride DW, Flores JJ, Tang J, Zhang JH. Bliverdin reductase-a improves neurological function in a germinal matrix hemorrhage rat model. Neurobiol Dis. 2018;110:122–32.CrossRefPubMed
34.
Stewart IB, McKenzie DC. The human spleen during physiological stress. Sports Med. 2002;32:361–9.CrossRefPubMed
35.
del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879–94.CrossRefPubMed
36.
Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol. 1998;56:149–71.CrossRefPubMed
37.
Barone FC, Hillegass LM, Price WJ, White RF, Lee EV, Feuerstein GZ, Sarau HM, Clark RK, Griswold DE. Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity assay and histologic verification. J Neurosci Res. 1991;29:336–45.CrossRefPubMed
38.
Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6.CrossRefPubMedPubMedCentral
39.
Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, Vandenbark AA, Hurn PD. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176:6523–31.CrossRefPubMed
40.
41.
Sun J, Steenbergen C, Murphy E. S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal. 2006;8:1693–705.CrossRefPubMedPubMedCentral
42.
Into T, Inomata M, Nakashima M, Shibata K, Hacker H, Matsushita K. Regulation of MyD88-dependent signaling events by S nitrosylation retards toll-like receptor signal transduction and initiation of acute-phase immune responses. Mol Cell Biol. 2008;28:1338–47.CrossRefPubMed
43.
Metadata
Title
Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway
Authors
Yiting Zhang
Yan Ding
Tai Lu
Yixin Zhang
Ningbo Xu
Devin W. McBride
Jiping Tang
John H. Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1155-z

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