Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α

Franca Orsini, Stefano Fumagalli, Eszter Császár, Krisztina Tóth, Daiana De Blasio, Rosalia Zangari, Nikolett Lénárt, Ádám Dénes, Maria-Grazia De Simoni

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2678-2690
Number of pages13
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 2018

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Mannose-Binding Lectin
Brain Ischemia
Interleukin-1
Blood Vessels
Blood Platelets
Phenotype
Ischemia
Brain Injuries
Chemokine CXCL1
Mannose-Binding Lectin Complement Pathway
Interleukin-1 Receptors
Brain
Thromboplastin
Photons
Endothelium
Microscopy
Cell Death
Anti-Inflammatory Agents
Endothelial Cells
Oxygen

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Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α. / Orsini, Franca; Fumagalli, Stefano; Császár, Eszter; Tóth, Krisztina; De Blasio, Daiana; Zangari, Rosalia; Lénárt, Nikolett; Dénes, Ádám; De Simoni, Maria-Grazia.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 38, No. 11, 11.2018, p. 2678-2690.

Research output: Contribution to journalArticle

Orsini, Franca ; Fumagalli, Stefano ; Császár, Eszter ; Tóth, Krisztina ; De Blasio, Daiana ; Zangari, Rosalia ; Lénárt, Nikolett ; Dénes, Ádám ; De Simoni, Maria-Grazia. / Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2018 ; Vol. 38, No. 11. pp. 2678-2690.
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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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AU - Orsini, Franca

AU - Fumagalli, Stefano

AU - Császár, Eszter

AU - Tóth, Krisztina

AU - De Blasio, Daiana

AU - Zangari, Rosalia

AU - Lénárt, Nikolett

AU - Dénes, Ádám

AU - De Simoni, Maria-Grazia

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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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SN - 1079-5642

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