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 1/2013

Open Access 01-12-2013 | Review

Leukocyte infiltration in experimental stroke

Authors: Nina Vindegaard Grønberg, Flemming Fryd Johansen, Uffe Kristiansen, Henrik Hasseldam

Published in: Journal of Neuroinflammation | Issue 1/2013

Login to get access

Abstract

Stroke is one of the leading causes of death worldwide. At present, the only available treatment is thrombolysis, which should be initiated no later than 4.5 hours after onset of symptoms. Several studies have shown that an attenuation of the inflammatory response in relation to stroke could widen the therapeutic window. However, the immune system has important functions following infarction, such as removal of dead cells and the subsequent astrocytosis as well as prevention of post-ischemic infection. Hence, detailed knowledge concerning the temporal profile of leukocyte infiltration is necessary in order to develop new and effective treatments.
The purpose of this review is to determine the temporal profile of leukocyte (neutrophil granulocytes, macrophages and T-cells) infiltration following experimental stroke. We found that the number of neutrophil granulocytes peaks between day 1 and 3 after experimental stroke, with short occlusion times (30 and 60 minutes of middle cerebral artery occlusion (MCAO)) leading to a later peak in response (P <0.001). Macrophages/microglia were found to peak later than day 3 and stay in the infarcted area for longer time periods, whereas duration of occlusion had no influence on the temporal infiltration (P = 0.475). Studies on T-cell infiltration are few; however, a tendency towards infiltration peak at later time points (from day 4 onwards) was seen.
This review provides a framework for the instigation of post-stroke anti-inflammatory treatment, which could prove beneficial and widen the therapeutic window compared to current treatment options.
Literature
1.
World Health Organization (WHO): The Top 10 Causes of Death. Fact sheet number 310. Geneva: WHO; 2011.
2.
3.
American Stroke Association: Acute and Preventive Stroke Treatments. Dallas, TX: American Stroke Association; 2012.
4.
Brait VH, Arumugam TV, Drummond GR, Sobey CG: Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J Cereb Blood Flow and Metab 2012, 32:598–611.CrossRef
5.
Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neuroscience 1999,22(9):391–397.CrossRef
6.
Yilmaz G, Granger DN: Leukocyte recruitment and ischemic brain injury. Neuromolecular Med 2010, 12:193–204.CrossRefPubMed
7.
Brea D, Sobrino T, Ramos-Cabrer P, Castillo J: Inflammatory and neuroimmunomodulatory changes in acute cerebral ischemia. Cerebrovasc Dis 2009,27(Suppl 1):48–64.CrossRefPubMed
8.
9.
Muir KW, Tyrrell P, Sattar N, Warburton E: Inflammation and ischaemic stroke. Curr Opin Neurol 2007, 20:334–342.CrossRefPubMed
10.
Veldhuis WB, Derksen JW, Floris S, Van Der Meide PH, De Vries HE, Schepers J, Vos IM, Dijkstra CD, Kappelle LJ, Nicolay K, Bär PR: Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat. J Cereb Blood Flow Metab 2003, 23:1029–1039.CrossRefPubMed
11.
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, 29:336–345.CrossRefPubMed
12.
Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K: Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab 1995, 15:941–947.CrossRefPubMed
13.
Satoh S, Kobayashi T, Hitomi A, Ikegaki I, Suzuki Y, Shibuya M, Yoshida J, Asano T: Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction. Jpn J Pharmacol 1999, 80:41–48.CrossRefPubMed
14.
Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A: Pivotal role of cerebral interleukin-17-producing gammadelta T cells in the delayed phase of ischemic brain injury. Nat Med 2009, 15:946–950.CrossRefPubMed
15.
Campanella M, Sciorati C, Tarozzo G, Beltramo M: Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 2002, 33:586–592.CrossRefPubMed
16.
17.
18.
Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G: Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 2010, 115:3835–3842.CrossRefPubMed
19.
Linfert D, Chowdhry T, Rabb H: Lymphocytes and ischemia-reperfusion injury. Transplantation Rev (Orlando) 2009, 23:1–10.CrossRef
20.
Yilmaz G, Arumugam TV, Stokes KY, Granger DN: Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 2006, 113:2105–2112.CrossRefPubMed
21.
Hallenbeck JM, Hansson GK, Becker KJ: Immunology of ischemic vascular disease: plaque to attack. Trends Immunol 2005, 26:550–556.CrossRefPubMed
22.
Moore S, Thanos S: The concept of microglia in relation to central nervous system disease and regeneration. Prog Neurobiol 1996, 48:441–460.CrossRefPubMed
23.
Marks L, Carswell HV, Peters EE, Graham DI, Patterson J, Dominiczak AF, Macrae IM: Characterization of the microglial response to cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension 2001, 38:116–122.CrossRefPubMed
24.
Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE, Guida E, Broughton BR, Drummond GR, Sobey CG: Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 2010, 30:1306–1317.CrossRefPubMedPubMedCentral
25.
Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, Allan SM: Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 2007, 27:1941–1953.CrossRefPubMed
26.
Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ: Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 1994, 144:188–199.PubMedPubMedCentral
27.
Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y, Urabe T: Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 2006, 26:402–413.CrossRefPubMed
28.
Zhang RL, Chopp M, Chen H, Garcia JH: Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurol Sci 1994, 125:3–10.CrossRefPubMed
29.
Louis J, Pellegrino AJC: A Stereotaxic Atlas of the Rat Brain. New York, NY: Appleton-Century-Crofts; 1967.
30.
31.
Schilling M, Strecker JK, Schabitz WR, Ringelstein EB, Kiefer R: Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience 2009, 161:806–812.CrossRefPubMed
32.
Schilling M, Strecker JK, Ringelstein EB, Schäbitz WR, Kiefer R: The role of CC chemokine receptor 2 on microglia activation and blood-borne cell recruitment after transient focal cerebral ischemia in mice. Brain Res 2009, 1289:79–84.CrossRefPubMed
33.
Jin R, Song Z, Yu S, Piazza A, Nanda A, Penninger JM, Granger DN, Li G: Phosphatidylinositol-3-kinase gamma plays a central role in blood–brain barrier dysfunction in acute experimental stroke. Stroke 2011, 42:2033–2044.CrossRefPubMedPubMedCentral
34.
Stevens SL, Bao J, Hollis J, Lessov NS, Clark WM, Stenzel-Poore MP: The use of flow cytometry to evaluate temporal changes in inflammatory cells following focal cerebral ischemia in mice. Brain Res 2002, 932:110–119.CrossRefPubMed
35.
Inamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000, 109:66–74.CrossRefPubMed
36.
Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, Kogure K: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 1994, 25:1469–1475.CrossRefPubMed
37.
Hiraga N, Adachi N, Liu K, Nagaro T, Arai T: Suppression of inflammatory cell recruitment by histamine receptor stimulation in ischemic rat brains. Eur J Pharmacol 2007, 557:236–244.CrossRefPubMed
38.
Kim BJ, Kim MJ, Park JM, Lee SH, Kim YJ, Ryu S, Kim YH, Yoon BW: Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat. J Neurol Sci 2009, 279:70–75.CrossRefPubMed
39.
Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA: Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 2002, 114:1081–1090.CrossRefPubMed
40.
Mu S, Ouyang L, Liu B, Qu H, Zhu Y, Li K, Lei W: Relationship between inflammatory reaction and ischemic injury of caudate-putamen in rats: inflammatory reaction and brain ischemia. Anat Sci Int 2011, 86:86–97.CrossRefPubMed
41.
Schroeter M, Jander S, Witte OW, Stoll G: Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. J Neuroimmunol 1994, 55:195–203.CrossRefPubMed
42.
Choe CU, Lardong K, Gelderblom M, Ludewig P, Leypoldt F, Koch-Nolte F, Gerloff C, Magnus T: CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia. PLoS One 2011, 6:e19046.CrossRefPubMedPubMedCentral
43.
Liesz A, Zhou W, Mracskó É, Karcher S, Bauer H, Schwarting S, Sun L, Bruder D, Stegemann S, Cerwenka A, Sommer C, Dalpke AH, Veltkamp R: Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 2011, 134:704–720.CrossRefPubMed
44.
Takata M, Nakagomi T, Kashiwamura S, Nakano-Doi A, Saino O, Nakagomi N, Okamura H, Mimura O, Taguchi A, Matsuyama T: Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke. Cell Death Differ 2012, 19:756–767.CrossRefPubMed
45.
Li GZ, Zhong D, Yang LM, Sun B, Zhong ZH, Yin YH, Cheng J, Yan BB, Li HL: Expression of interleukin-17 in ischemic brain tissue. Scand J Immunol 2005, 62:481–486.CrossRefPubMed
46.
Rosell A, Cuadrado E, Ortega-Aznar A, Hernández-Guillamon M, Lo EH, Montaner J: MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008, 39:1121–1126.CrossRefPubMed
47.
McCarter JF, McGregor AL, Jones PA, Sharkey J: FK 506 protects brain tissue in animal models of stroke. Transplant Proc 2001, 33:2390–2392.CrossRefPubMed
48.
Harris AK, Ergul A, Kozak A, Machado LS, Johnson MH, Fagan SC: Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke. BMC Neurosci 2005, 6:49.CrossRefPubMedPubMedCentral
49.
Fassbender K, Ragoschke A, Kühl S, Szabo K, Fatar M, Back W, Bertsch T, Kreisel S, Hennerici M: Inflammatory leukocyte infiltration in focal cerebral ischemia: unrelated to infarct size. Cerebrovasc Dis 2002, 13:198–203.CrossRefPubMed
50.
Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, Meisel A, Meisel C: Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 2009, 158:1184–1193.CrossRefPubMed
51.
Clark WM, Lessov N, Lauten JD, Hazel K: Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat. J Mol Neurosci 1997, 9:103–108.CrossRefPubMed
52.
Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Shudou M, Ii C, Takahashi H, Imai Y, Tanaka J: Antibodies to CD11b, CD68, and lectin label neutrophils rather than microglia in traumatic and ischemic brain lesions. J Neurosci Res 2007, 85:994–1009.CrossRefPubMed
53.
54.
55.
Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R: Regulatory T cells are key cerebroprotectiveimmunomodulators in acute experimental stroke. Nat Med 2009, 15:192–199.CrossRefPubMed
56.
Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB: Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195. Neurology 2000, 55:1052–1054.CrossRefPubMed
57.
Yilmaz A, Fuchs T, Dietel B, Altendorf R, Cicha I, Stumpf C, Schellinger PD, Blümcke I, Schwab S, Daniel WG, Garlichs CD, Kollmar R: Transient decrease in circulating dendritic cell precursors after acute stroke: potential recruitment into the brain. Clin Sci (Lond) 2009, 118:147–157.CrossRef
58.
Sarchielli P, Nardi K, Chiasserini D, Eusebi P, Tantucci M, Di Piero V, Altieri M, Marini C, Russo T, Silvestrini M, Paolino I, Calabresi P, Parnetti L: Immunological profile of silent brain infarction and lacunar stroke. PLoS One 2013, 8:e68428.CrossRefPubMedPubMedCentral
59.
Li G, Wang X, Huang LH, Wang Y, Hao JJ, Ge X, Xu XY: Cytotoxic function of CD8+ T lymphocytes isolated from patients with acute severe cerebral infarction: an assessment of stroke-induced immunosuppression. BMC Immunol 2013, 14:1.CrossRefPubMedPubMedCentral
60.
Haley PJ: Species differences in the structure and function of the immune system. Toxicology 2003, 188:49–71.CrossRefPubMed
61.
Smialowicz RJ, Riddle MM, Williams WC, Diliberto JJ: Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on humoral immunity and lymphocyte subpopulations: differences between mice and rats. Toxicol Appl Pharmacol 1994, 124:248–256.CrossRefPubMed
62.
Dhabhar FS, Mcewen BS, Spencer RL: Stress response, adrenal steroid receptor levels and corticosteroid-binding globulin levels–a comparison between Sprague–Dawley, Fischer 344 and Lewis rats. Brain Res 1993, 616:89–98.CrossRefPubMed
63.
Griffin AC, Whitacre CC: Sex and strain differences in the circadian rhythm fluctuation of endocrine and immune function in the rat: implications for rodent models of autoimmune disease. J Neuroimmunol 1991, 35:53–64.CrossRefPubMed
64.
Hoffman PM, Powers JM, Weise MJ, Brostoff SW: Experimental allergic neuritis. I. Rat strain differences in the response to bovine myelin antigens. Brain Res 1980, 195:355–362.CrossRefPubMed
65.
Morselt AF, Leene W, De Groot C, Kipp JB, Evers M, Roelofsen AM, Bosch KS: Differences in immunological susceptibility to cadmium toxicity between two rat strains as demonstrated with cell biological methods. Effect of cadmium on DNA synthesis of thymus lymphocytes. Toxicology 1988, 48:127–139.CrossRefPubMed
66.
Gemmell E, Winning TA, Carter CL, Ford PJ, Bird PS, Ashman RB, Grieco DA, Seymour GJ: Differences in mouse strain influence leukocyte and immunoglobulin phenotype response to Porphyromonas gingivalis. Oral Microbiol Immunol 2003, 18:364–370.CrossRefPubMed
67.
Sellers RS, Clifford CB, Treuting PM, Brayton C: Immunological variation between inbred laboratory mouse strains: points to consider in phenotyping genetically immunomodified mice. Vet Pathol 2012, 49:32–43.CrossRefPubMed
68.
Mestas J, Hughes CC: Of mice and not men: differences between mouse and human immunology. J Immunol 2004, 172:2731–2738.CrossRefPubMed
Metadata
Title
Leukocyte infiltration in experimental stroke
Authors
Nina Vindegaard Grønberg
Flemming Fryd Johansen
Uffe Kristiansen
Henrik Hasseldam
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2013
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-10-115

Other articles of this Issue 1/2013

Journal of Neuroinflammation 1/2013 Go to the issue

Research

Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation

Research

Amyloid-β peptide-induced extracellular S100A9 depletion is associated with decrease of antimicrobial peptide activity in human THP-1 monocytes

Research

Treatment with an anti-CD11d integrin antibody reduces neuroinflammation and improves outcome in a rat model of repeated concussion

Research

HIV infection and drugs of abuse: role of acute phase proteins

Research

Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve

Research

Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury