The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome

Journal of Neuroinflammation

Hans Worthmann¹  Karin Weissenborn³  Ralf Lichtinghagen²  Henning Pflugrad¹  Ramona Schuppner¹  Meike Dirks¹  Anita B Tryc¹  Gerrit M Grosse¹ 

[1]Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

[2]Department of Clinical Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

[3]Center for Systems Neuroscience (ZSN), Bünteweg 2, 30559 Hannover, Germany

关键词: Severity;    Outcome;    Ischemic stroke;    Inflammation;    Fractalkine;    CX3CL1;    Biomarker;   

Others  :  804799
DOI  :  10.1186/1742-2094-11-74

 received in 2013-12-24, accepted in 2014-03-28,  发布年份 2014

【 摘 要 】

Background

The chemokine fractalkine (CX3CL1, FKN) is involved in neural-microglial interactions and is regarded as neuroprotective according to several in vivo studies of inflammatory and degenerative states of the brain. Recently, an association with outcome in human ischemic stroke has been proposed. In this study, we aimed to investigate the temporal pattern of FKN levels in acute ischemic stroke in relation to stroke severity and outcome.

Methods

FKN levels were measured in plasma specimens of fifty-five patients with acute ischemic stroke. Blood was available for time points 6 hours (h), 12 h, 3 days (d), 7 d and 90 d after stroke onset. Clinical outcome was evaluated using the modified Rankin Scale (mRS) at 7 d and 90 d.

Results

The time course of FKN significantly differs depending on stroke severity, with higher FKN levels linked to a lower severity. FKN levels in patients with moderate to severe strokes differ significantly from controls. In outcome analysis, we found an association of dynamics of FKN with clinical outcome. Decrease of FKN is pronounced in patients with worse outcome. Multivariate analysis including stroke severity and stroke etiology revealed that deltaFKN between 6 h and 3 d is independently associated with mRS at 90 d. In addition deltaFKN is inversely correlated with the extent of brain damage, as measured by S100B.

Conclusions

FKN dynamics are independently associated with stroke outcome. Further studies might give insight on whether FKN is actively involved in the inflammatory cascade after acute ischemic stroke.

【 授权许可】

   
2014 Grosse et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ: A new class of membrane-bound chemokine with a CX3C motif. Nature 1997, 385:640-644.
• [2]Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen K-J, Rose-John S, Ludwig A: The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 2003, 102:1186-1195.
• [3]Matsunawa M, Isozaki T, Odai T, Yajima N, Takeuchi HT, Negishi M, Ide H, Adachi M, Kasama T: Increased serum levels of soluble fractalkine (CX3CL1) correlate with disease activity in rheumatoid vasculitis. Arthritis Rheum 2006, 54:3408-3416.
• [4]Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT: CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 2010, 177:2549-2562.
• [5]Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J Neuroinflammation 2011, 8:9. BioMed Central Full Text
• [6]Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 1998, 95:10896-10901.
• [7]Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J, Kawaguchi N, Kume T, Akaike A, Satoh M: Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? FEBS Lett 1998, 429:167-172.
• [8]Maciejewski-Lenoir D, Chen S, Feng L, Maki R, Bacon KB: Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. J Immunol 1999, 163:1628-1635.
• [9]Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E, Perego C, De Simoni MG, Fredholm BB, Eusebi F, Limatola C: CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci 2011, 31:16327-16335.
• [10]Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ, Dénes A, Halász J, Környei Z, Kovács KJ: Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab 2008, 28:1707-1721.
• [11]Soriano SG, Amaravadi LS, Wang YF, Zhou H, Yu GX, Tonra JR, Fairchild-Huntress V, Fang Q, Dunmore JH, Huszar D, Pan Y: Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J Neuroimmunol 2002, 125:59-65.
• [12]Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee J-CC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006, 9:917-924.
• [13]Sunnemark D, Eltayeb S, Nilsson M, Wallström E, Lassmann H, Olsson T, Berg A-L, Ericsson-Dahlstrand A: CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin. J Neuroinflammation 2005, 2:17. BioMed Central Full Text
• [14]Donohue MM, Cain K, Zierath D, Shibata D, Tanzi PM, Becker KJ: Higher plasma fractalkine is associated with better 6-month outcome from ischemic stroke. Stroke 2012, 43:2300-2306.
• [15]Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Dengler R, Lichtinghagen R, Weissenborn K: The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010, 30:85-92.
• [16]Coutts SB, Barber PA, Demchuk AM, Hill MD, Pexman JHW, Hudon ME, Buchan AM: Mild neurological symptoms despite middle cerebral artery occlusion. Stroke 2004, 35:469-471.
• [17]Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, Investigators E: Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008, 359:1317-1329.
• [18]Dengler R, Diener HC, Schwartz A, Grond M, Schumacher H, Machnig T, Eschenfelder CC, Leonard J, Weissenborn K, Kastrup A, Haberl R, Investigators E: Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010, 9:159-166.
• [19]Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993, 24:35-41.
• [20]Mizuno T, Kawanokuchi J, Numata K, Suzumura A: Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 2003, 979:65-70.
• [21]Zujovic V, Benavides J, Vigé X, Carter C, Taupin V: Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 2000, 29:305-315.
• [22]Boehme SA, Lio FM, Maciejewski-Lenoir D, Bacon KB, Conlon PJ: The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia. J Immunol 2000, 165:397-403.
• [23]Meucci O, Fatatis A, Simen AA, Miller RJ: Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci U S A 2000, 97:8075-8080.
• [24]Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T: Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009, 40:1849-1857.
• [25]Grønberg NV, Johansen FF, Kristiansen U, Hasseldam H: Leukocyte infiltration in experimental stroke. J Neuroinflammation 2013, 10:115. BioMed Central Full Text
• [26]Urra X, Villamor N, Amaro S, Gomez-Choco M, Obach V, Oleaga L, Planas AM, Chamorro A: Monocyte subtypes predict clinical course and prognosis in human stroke. J Cereb Blood Flow Metab 2009, 29:994-1002.
• [27]Bao Y, Kim E, Bhosle S, Mehta H, Cho S: A role for spleen monocytes in post-ischemic brain inflammation and injury. J Neuroinflammation 2010, 7:92. BioMed Central Full Text
• [28]Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ: The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007, 204:3037-3047.
• [29]Nahrendorf M, Pittet MJ, Swirski FK: Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 2010, 121:2437-2445.
• [30]Stolla M, Pelisek J, von Bruhl ML, Schafer A, Barocke V, Heider P, Lorenz M, Tirniceriu A, Steinhart A, Bauersachs J, Bray PF, Massberg S, Schulz C, von Brühl M-L, Schäfer A: Fractalkine is expressed in early and advanced atherosclerotic lesions and supports monocyte recruitment via CX3CR1. PLoS One 2012, 7:e43572.
• [31]Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ: Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007, 117:185-194.
• [32]Wong BW, Wong D, McManus BM: Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol 2002, 11:332-338.
• [33]Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z: Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003, 107:1009-1016.
• [34]Lesnik P, Haskell CA, Charo IF: Decreased atherosclerosis in CX3 CR1-/-mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003, 111:333-340.
• [35]Saederup N, Chan L, Lira SA, Charo IF: Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/-mice: evidence for independent chemokine functions in atherogenesis. Circulation 2008, 117:1642-1648.
• [36]Richter B, Koller L, Hohensinner PJ, Rychli K, Zorn G, Goliasch G, Berger R, Mortl D, Maurer G, Huber K, Pacher R, Wojta J, Hulsmann M, Niessner A: Fractalkine is an independent predictor of mortality in patients with advanced heart failure. Thromb Haemost 2012, 108:1220-1227.