Orsini, Franca and Fumagalli, Stefano and Császár, Eszter and Tóth, Krisztina and De Blasio, Daiana and Lénárt, Nikolett and Dénes, Ádám (2018) Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 38 (11). pp. 2678-2690. ISSN 1079-5642
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Mannose-BindingLectinDrivesPlateletInflammatoryPhenotypeandVascularDamageAfterCerebralIschemiainMiceviaIL.pdf Download (1MB) | Preview |
Abstract
Objective- Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet. Approach and Results- Here we show that MBL-deficient (MBL-/-) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL-/- mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL-/- mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage. Conclusions- We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.
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| Additional Information: | Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Milano, Italy Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary Cited By :3 Export Date: 29 November 2019 CODEN: ATVBF Correspondence Address: De Simoni, M.-G.; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Italy; email: desimoni@marionegri.it Chemicals/CAS: intercellular adhesion molecule 1, 126547-89-5; thrombomodulin, 112049-68-0; Chemokine CXCL1; CXCL1 protein, human; IL1B protein, mouse; IL1R1 protein, mouse; Interleukin-1alpha; Interleukin-1beta; Mannose-Binding Lectin; Receptors, Interleukin-1 Type I Funding details: KTIA_13_NAP-A-I/2 Funding details: K109743 Funding details: ERC-CoG 724994 Funding details: Fondazione Cariplo, 2015–1003, 2012–0590 Funding text 1: F. Orsini was funded by fellowship in memory of Amalia Ghezzi. S. Fumagalli and D. De Blasio were funded by fellowship from Fondazione Cariplo (grant No. 2012–0590 and 2015–1003). Funding for A. Dénes was provided by OTKA K109743, the Momentum Program of the Hungarian Academy of Sciences, ERC-CoG 724994, and the Hungarian Brain Research Program KTIA_13_NAP-A-I/2. Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Milano, Italy Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary Cited By :8 Export Date: 29 July 2020 CODEN: ATVBF Correspondence Address: De Simoni, M.-G.; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Italy; email: desimoni@marionegri.it Chemicals/CAS: intercellular adhesion molecule 1, 126547-89-5; thrombomodulin, 112049-68-0; Chemokine CXCL1; CXCL1 protein, human; IL1B protein, mouse; IL1R1 protein, mouse; Interleukin-1alpha; Interleukin-1beta; Mannose-Binding Lectin; Receptors, Interleukin-1 Type I Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Hungarian Scientific Research Fund, OTKA, K109743 Funding details: Fondazione Cariplo, 2015–1003, 2012–0590 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: F. Orsini was funded by fellowship in memory of Amalia Ghezzi. S. Fumagalli and D. De Blasio were funded by fellowship from Fondazione Cariplo (grant No. 2012–0590 and 2015–1003). Funding for A. Dénes was provided by OTKA K109743, the Momentum Program of the Hungarian Academy of Sciences, ERC-CoG 724994, and the Hungarian Brain Research Program KTIA_13_NAP-A-I/2. Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Milano, Italy Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary Cited By :8 Export Date: 30 July 2020 CODEN: ATVBF Correspondence Address: De Simoni, M.-G.; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Italy; email: desimoni@marionegri.it Chemicals/CAS: intercellular adhesion molecule 1, 126547-89-5; thrombomodulin, 112049-68-0; Chemokine CXCL1; CXCL1 protein, human; IL1B protein, mouse; IL1R1 protein, mouse; Interleukin-1alpha; Interleukin-1beta; Mannose-Binding Lectin; Receptors, Interleukin-1 Type I Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Hungarian Scientific Research Fund, OTKA, K109743 Funding details: Fondazione Cariplo, 2015–1003, 2012–0590 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: F. Orsini was funded by fellowship in memory of Amalia Ghezzi. S. Fumagalli and D. De Blasio were funded by fellowship from Fondazione Cariplo (grant No. 2012–0590 and 2015–1003). Funding for A. Dénes was provided by OTKA K109743, the Momentum Program of the Hungarian Academy of Sciences, ERC-CoG 724994, and the Hungarian Brain Research Program KTIA_13_NAP-A-I/2. Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Milano, Italy Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary Cited By :8 Export Date: 31 July 2020 CODEN: ATVBF Correspondence Address: De Simoni, M.-G.; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Mario Negri Institute, via Giuseppe La Masa,19, Italy; email: desimoni@marionegri.it Chemicals/CAS: intercellular adhesion molecule 1, 126547-89-5; thrombomodulin, 112049-68-0; Chemokine CXCL1; CXCL1 protein, human; IL1B protein, mouse; IL1R1 protein, mouse; Interleukin-1alpha; Interleukin-1beta; Mannose-Binding Lectin; Receptors, Interleukin-1 Type I Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Hungarian Scientific Research Fund, OTKA, K109743 Funding details: Fondazione Cariplo, 2015–1003, 2012–0590 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: F. Orsini was funded by fellowship in memory of Amalia Ghezzi. S. Fumagalli and D. De Blasio were funded by fellowship from Fondazione Cariplo (grant No. 2012–0590 and 2015–1003). Funding for A. Dénes was provided by OTKA K109743, the Momentum Program of the Hungarian Academy of Sciences, ERC-CoG 724994, and the Hungarian Brain Research Program KTIA_13_NAP-A-I/2. |
| Uncontrolled Keywords: | ENDOTHELIUM; PLATELETS; Interleukin-1; stroke; MANNOSE-BINDING LECTIN; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 23 Sep 2020 05:40 |
| Last Modified: | 23 Sep 2020 05:40 |
| URI: | http://real.mtak.hu/id/eprint/114126 |
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