Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1).
- Liberale L Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, 8952 Schlieren, Switzerland.
- Bertolotto M First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.
- Minetti S First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.
- Contini P Clinical Immunology, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.
- Verzola D Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.
- Ameri P IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy.
- Ghigliotti G IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy.
- Pende A IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy.
- Camici GG Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, 8952 Schlieren, Switzerland.
- Carbone F First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.
- Montecucco F First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.
- 2020-09-26
Published in:
- International journal of molecular sciences. - 2020
English
Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden chamber migration assay and checkerboard analysis we showed a dose-dependent chemotactic effect of r-TPA with a maximum effect reached by 0.03 mg/mL (0.003-1 mg/mL). Pre-incubation with MAP kinases inhibitors allowed the identification of PI3K/Akt, but not ERK1/2 as the intracellular pathway mediating the observed effects. Furthermore, by means of real-time PCR, immunocytochemistry and cytofluorimetry we demonstrated that the r-tPA receptor low density lipoprotein receptor-related protein 1 (LRP-1) is synthetized and expressed by neutrophils in response to r-tPA and TNF-α. Inhibition of LRP-1 by receptor-associated protein (RAP), prevented r-tPA-mediated F-actin polymerization, migration and signal through Akt but not ERK1/2. Lastly, also neutrophil degranulation in response to r-tPA seems to be mediated by LRP-1 under adhesion conditions. In conclusion, we show that r-tPA induces neutrophil chemotaxis through LRP-1/Akt pathway. Blunting r-tPA-mediated neutrophil activation might be beneficial as an adjuvant therapy to thrombolysis in this setting.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.3390/ijms21197014
- PMID 32977685
- Persistent URL
- https://sonar.rero.ch/global/documents/10480
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