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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Fluids and Barriers of the CNS
Published in: Fluids and Barriers of the CNS 1/2017

Open Access 01-12-2017 | Research

Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus

Authors: Gakwaya Habiyaremye, Diego M. Morales, Clinton D. Morgan, James P. McAllister, Travis S. CreveCoeur, Rowland H. Han, Mohamed Gabir, Brandon Baksh, Deanna Mercer, David D. Limbrick Jr.

Published in: Fluids and Barriers of the CNS | Issue 1/2017

Login to get access

Abstract

Background

Neuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF).

Methods

Lumbar CSF levels of key cytokines (IL-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-β1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined.

Results

Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1β, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1β and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils.

Conclusions

Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.
Literature
1.
2.
Murphy BP, Inder TE, Rooks V, Taylor GA, Anderson NJ, Mogridge N, Horwood LJ, Volpe JJ. Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch Dis Child Fetal Neonatal Ed. 2002;87:F37–41.CrossRefPubMedPubMedCentral
3.
Tsitouras V, Sgouros S. Infantile posthemorrhagic hydrocephalus. Child’s Nerv Syst. 2011;27:1595–608.CrossRef
4.
Cherian S, Whitelaw A, Thoresen M, Love S. The pathogenesis of neonatal post-hemorrhagic hydrocephalus. Brain Pathol. 2004;14:305–11.CrossRefPubMed
5.
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
6.
Strahle J, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G. Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res. 2012;3:25–38.CrossRefPubMedPubMedCentral
7.
Takizawa T, Tada T, Kitazawa K, Tanaka Y, Hongo K, Kameko M, Uemura KI. Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res. 2001;23:724–30.CrossRefPubMed
8.
Robinson S. Neonatal posthemorrhagic hydrocephalus from prematurity: pathophysiology and current treatment concepts. J Neurosurg Pediatr. 2012;9:242–58.CrossRefPubMed
9.
Botfield H, Gonzalez AM, Abdullah O, Skjolding AD, Berry M, McAllister JP 2nd, Logan A. Decorin prevents the development of juvenile communicating hydrocephalus. Brain. 2013;136:2842–58.CrossRefPubMed
10.
Chow LC, Soliman A, Zandian M, Danielpour M, Krueger RC Jr. Accumulation of transforming growth factor-beta2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus. Biol Neonate. 2005;88:1–11.CrossRefPubMed
11.
Heep A, Stoffel-Wagner B, Bartmann P, Benseler S, Schaller C, Groneck P, Obladen M, Felderhoff-Mueser U. Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus. Pediatr Res. 2004;56:768–74.CrossRefPubMed
12.
Savman K, Blennow M, Hagberg H, Tarkowski E, Thoresen M, Whitelaw A. Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation. Acta Paediatr. 2002;91:1357–63.CrossRefPubMed
13.
Schmitz T, Heep A, Groenendaal F, Huseman D, Kie S, Bartmann P, Obladen M, Felderhoff-Muser U. Interleukin-1beta, interleukin-18, and interferon-gamma expression in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus—markers of white matter damage? Pediatr Res. 2007;61:722–6.CrossRefPubMed
14.
Yung YC, Mutoh T, Lin ME, Noguchi K, Rivera RR, Choi JW, Kingsbury MA, Chun J. Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci Transl Med. 2011;3:99ra87.CrossRefPubMedPubMedCentral
15.
Morales DM, Townsend RR, Malone JP, Ewersmann CA, Macy EM, Inder TE, Limbrick DD Jr. Alterations in protein regulators of neurodevelopment in the cerebrospinal fluid of infants with posthemorrhagic hydrocephalus of prematurity. Mol Cell Proteom. 2012;11(M111):011973.
16.
Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843:2563–82.CrossRefPubMed
17.
Trifilo MJ, Lane TE. Adenovirus-mediated expression of CXCL10 in the central nervous system results in T-cell recruitment and limited neuropathology. J Neurovirol. 2003;9:315–24.CrossRefPubMed
18.
Trifilo MJ, Lane TE. The CC chemokine ligand 3 regulates CD11c+ CD11b+ CD8alpha− dendritic cell maturation and activation following viral infection of the central nervous system: implications for a role in T cell activation. Virology. 2004;327:8–15.CrossRefPubMed
19.
Klein RS. Regulation of neuroinflammation: the role of CXCL10 in lymphocyte infiltration during autoimmune encephalomyelitis. J Cell Biochem. 2004;92:213–22.CrossRefPubMed
20.
Karman J, Chu HH, Co DO, Seroogy CM, Sandor M, Fabry Z. Dendritic cells amplify T cell-mediated immune responses in the central nervous system. J Immunol. 2006;177:7750–60.CrossRefPubMed
21.
Israelsson C, Bengtsson H, Kylberg A, Kullander K, Lewen A, Hillered L, Ebendal T. Distinct cellular patterns of upregulated chemokine expression supporting a prominent inflammatory role in traumatic brain injury. J Neurotrauma. 2008;25:959–74.CrossRefPubMed
22.
Itoh T, Satou T, Ishida H, Nishida S, Tsubaki M, Hashimoto S, Ito H. The relationship between SDF-1alpha/CXCR4 and neural stem cells appearing in damaged area after traumatic brain injury in rats. Neurol Res. 2009;31:90–102.CrossRefPubMed
23.
24.
Morales DM, Silver SA, Morgan CD, Mercer D, Inder TE, Holtzman DM, Wallendorf MJ, Rao R, McAllister JP, Limbrick DD Jr. Lumbar cerebrospinal fluid biomarkers of posthemorrhagic hydrocephalus of prematurity: amyloid precursor protein, soluble amyloid precursor protein alpha, and L1 cell adhesion molecule. Neurosurgery. 2016;80(1):82–90.
25.
Wellons JC 3rd, Holubkov R, Browd SR, Riva-Cambrin J, Whitehead W, Kestle J, Kulkarni AV. Hydrocephalus Clinical Research N: the assessment of bulging fontanel and splitting of sutures in premature infants: an interrater reliability study by the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2013;11:12–4.CrossRefPubMed
26.
O’Hayon BB, Drake JM, Ossip MG, Tuli S, Clarke M. Frontal and occipital horn ratio: a linear estimate of ventricular size for multiple imaging modalities in pediatric hydrocephalus. Pediatr Neurosurg. 1998;29:245–9.CrossRefPubMed
27.
Baumeister FA, Pohl-Koppe A, Hofer M, Kim JO, Weiss M. IL-6 in CSF during ventriculitis in preterm infants with posthemorrhagic hydrocephalus. Infection. 2000;28:234–6.CrossRefPubMed
28.
Whitelaw A, Christie S, Pople I. Transforming growth factor-beta1: a possible signal molecule for posthemorrhagic hydrocephalus? Pediatr Res. 1999;46:576–80.CrossRefPubMed
29.
Szpecht D, Wiak K, Braszak A, Szymankiewicz M, Gadzinowski J. Role of selected cytokines in the etiopathogenesis of intraventricular hemorrhage in preterm newborns. Childs Nerv Syst. 2016;32:2097–103.CrossRefPubMedPubMedCentral
30.
Viscardi RM, Muhumuza CK, Rodriguez A, Fairchild KD, Sun CC, Gross GW, Campbell AB, Wilson PD, Hester L, Hasday JD. Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res. 2004;55:1009–17.CrossRefPubMed
31.
32.
Rochfort KD, Collins LE, McLoughlin A, Cummins PM. Tumour necrosis factor-alpha-mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin-6. J Neurochem. 2016;136:564–72.CrossRefPubMed
33.
Chung IY, Benveniste EN. Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol. 1990;144:2999–3007.PubMed
34.
Breder CD, Tsujimoto M, Terano Y, Scott DW, Saper CB. Distribution and characterization of tumor necrosis factor-alpha-like immunoreactivity in the murine central nervous system. J Comp Neurol. 1993;337:543–67.CrossRefPubMed
35.
Welser-Alves JV, Milner R. Microglia are the major source of TNF-alpha and TGF-beta1 in postnatal glial cultures; regulation by cytokines, lipopolysaccharide, and vitronectin. Neurochem Int. 2013;63:47–53.CrossRefPubMed
36.
Gahring LC, Carlson NG, Kulmar RA, Rogers SW. Neuronal expression of tumor necrosis factor alpha in the murine brain. Neuroimmunomodulation. 1996;3:289–303.CrossRefPubMed
37.
Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7:42–59.CrossRefPubMed
38.
Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78:151–6.CrossRefPubMed
39.
Rochfort KD, Cummins PM. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans. 2015;43:702–6.CrossRefPubMed
40.
Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochem Biophys Acta. 2016;1863:1218–27.CrossRefPubMed
41.
Seder RA, Paul WE, Davis MM. Fazekas de St Groth B: the presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992;176:1091–8.CrossRefPubMed
42.
Zundler S, Neurath MF. Interleukin-12: functional activities and implications for disease. Cytokine Growth Factor Rev. 2015;26:559–68.CrossRefPubMed
43.
44.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.CrossRefPubMed
45.
Ambrosini E, Remoli ME, Giacomini E, Rosicarelli B, Serafini B, Lande R, Aloisi F, Coccia EM. Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions. J Neuropathol Exp Neurol. 2005;64:706–15.CrossRefPubMed
46.
Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME. Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol. 1995;60:143–50.CrossRefPubMed
47.
Okamura T, Katayama T, Obinata C, Iso Y, Chiba Y, Kobayashi H, Yamada Y, Harashima H, Minami M. Neuronal injury induces microglial production of macrophage inflammatory protein-1alpha in rat corticostriatal slice cultures. J Neurosci Res. 2012;90:2127–33.CrossRefPubMed
48.
Chui R, Dorovini-Zis K. Regulation of CCL2 and CCL3 expression in human brain endothelial cells by cytokines and lipopolysaccharide. J Neuroinflammation. 2010;7:1.CrossRefPubMedPubMedCentral
49.
Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol. 1998;153:31–7.CrossRefPubMedPubMedCentral
50.
Stefini R, Catenacci E, Piva S, Sozzani S, Valerio A, Bergomi R, Cenzato M, Mortini P, Latronico N. Chemokine detection in the cerebral tissue of patients with posttraumatic brain contusions. J Neurosurg. 2008;108:958–62.CrossRefPubMed
51.
Helmy A, De Simoni MG, Guilfoyle MR, Carpenter KL, Hutchinson PJ. Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury. Prog Neurobiol. 2011;95:352–72.CrossRefPubMed
52.
Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31:658–70.CrossRefPubMed
53.
Holmin S, Hojeberg B. In situ detection of intracerebral cytokine expression after human brain contusion. Neurosci Lett. 2004;369:108–14.CrossRefPubMed
54.
55.
Sherry B, Tekamp-Olson P, Gallegos C, Bauer D, Davatelis G, Wolpe SD, Masiarz F, Coit D, Cerami A. Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta. J Exp Med. 1988;168:2251–9.CrossRefPubMed
56.
Wolpe SD, Davatelis G, Sherry B, Beutler B, Hesse DG, Nguyen HT, Moldawer LL, Nathan CF, Lowry SF, Cerami A. Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J Exp Med. 1988;167:570–81.CrossRefPubMed
57.
58.
Alt C, Laschinger M, Engelhardt B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol. 2002;32:2133–44.CrossRefPubMed
59.
Kivisakk P, Mahad DJ, Callahan MK, Sikora K, Trebst C, Tucky B, Wujek J, Ravid R, Staugaitis SM, Lassmann H, Ransohoff RM. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol. 2004;55:627–38.CrossRefPubMed
60.
Williams JL, Holman DW, Klein RS. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers. Front Cell Neurosci. 2014;8:154.CrossRefPubMedPubMedCentral
61.
Krumbholz M, Theil D, Steinmeyer F, Cepok S, Hemmer B, Hofbauer M, Farina C, Derfuss T, Junker A, Arzberger T, Sinicina I, Hartle C, Newcombe J, Hohlfeld R, Meinl E. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol. 2007;190:72–9.CrossRefPubMed
62.
Israelsson C, Bengtsson H, Lobell A, Nilsson LN, Kylberg A, Isaksson M, Wootz H, Lannfelt L, Kullander K, Hillered L, Ebendal T. Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders. Eur J Neurosci. 2010;31:852–63.CrossRefPubMed
63.
Helmy A, Antoniades CA, Guilfoyle MR, Carpenter KL, Hutchinson PJ. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury. PLoS ONE. 2012;7:e39677.CrossRefPubMedPubMedCentral
64.
Dorner BG, Dorner MB, Zhou X, Opitz C, Mora A, Guttler S, Hutloff A, Mages HW, Ranke K, Schaefer M, Jack RS, Henn V, Kroczek RA. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity. 2009;31:823–33.CrossRefPubMed
65.
66.
Gomez DG, DiBenedetto AT, Pavese AM, Firpo A, Hershan DB, Potts DG. Development of arachnoid villi and granulations in man. Acta Anat (Basel). 1982;111:247–58.
67.
Chazal J, Tanguy A, Irthum B, Janny P, Vanneuville G. Dilatation of the subarachnoid pericerebral space and absorption of cerebrospinal fluid in the infant. Anat Clin. 1985;7:61–6.CrossRefPubMed
68.
Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128:309–16.CrossRefPubMed
Metadata
Title
Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus
Authors
Gakwaya Habiyaremye
Diego M. Morales
Clinton D. Morgan
James P. McAllister
Travis S. CreveCoeur
Rowland H. Han
Mohamed Gabir
Brandon Baksh
Deanna Mercer
David D. Limbrick Jr.
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2017
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-017-0083-0

Other articles of this Issue 1/2017

Fluids and Barriers of the CNS 1/2017 Go to the issue

Review

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

Correction

Correction to: Correlation of CSF flow using phase-contrast MRI with ventriculomegaly and CSF opening pressure in mucopolysaccharidoses

Review

Blood–brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow

Review

The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse

Research

Hyperdynamic CSF motion profiles found in idiopathic normal pressure hydrocephalus and Alzheimer’s disease assessed by fluid mechanics derived from magnetic resonance images

Research

A change in brain white matter after shunt surgery in idiopathic normal pressure hydrocephalus: a tract-based spatial statistics study