Recombinant tissue plasminogen activator enhances microglial cell recruitment after stroke in mice.
The effect of recombinant human tissue plasminogen activator (rtPA) on neuroinflammation after stroke remains largely unknown. Here, we tested the effect of rtPA on expression of cellular adhesion molecules, chemokines, and cytokines, and compared those with levels of inflammatory cell recruitment, brain injury, and mortality over 3 days after transient middle cerebral artery occlusion (MCAO) in mice. Mortality was dramatically increased after rtPA treatment compared with saline treatment during the first day of reperfusion. Among the animals that survived, rtPA significantly increased CCL3 expression, microglia recruitment, and cerebral infarction 6 hours after MCAO. In contrast, the extent of neutrophils and macrophages infiltration in the brain was similar in both saline- and rtPA-treated animals. Recombinant human tissue plasminogen activator induced Il1b and Tnf expression, 6 and 72 hours after MCAO, respectively, and dramatically reduced interleukin 6 (IL-6) level 24 hours after reperfusion. A dose response study confirmed the effect of rtPA on CCL3 and Il1b expressions. The effect was similar at the doses of 1 and 10 mg/kg. In conclusion, we report for the first time that rtPA amplified microglia recruitment early after stroke in association with a rapid CCL3 production. This early response may take part in the higher susceptibility of rtPA-treated animals to reperfusion injury.
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.
Sébastien
S
Lenglet
1] First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy [2] Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.
Fabrizio
F
Montecucco
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Adam
A
Denes
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Graham
G
Coutts
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Emmanuel
E
Pinteaux
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.
François
F
Mach
1] Division of Neurosurgery, Department of Clinical Neurosciences, University Hospitals of Geneva, Geneva, Switzerland [2] Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland.
Karl
K
Schaller
1] Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland [2] Division of Intensive Care, Department of Anaesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland.
Yvan
Y
Gasche
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.
Jean-Christophe
JC
Copin
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D054405:Chemokine CCL3; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator