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1.
Nature ; 633(8029): 433-441, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39112714

RESUMEN

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.


Asunto(s)
Aterosclerosis , Inflamasomas , Placa Aterosclerótica , Recurrencia , Accidente Cerebrovascular , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Aterosclerosis/sangre , Aterosclerosis/complicaciones , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/metabolismo , Modelos Animales de Enfermedad , Proteínas de Unión al ADN/metabolismo , Trampas Extracelulares/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Neutrófilos/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Desoxirribonucleasas/metabolismo
2.
Cell Mol Life Sci ; 79(6): 323, 2022 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-35633384

RESUMEN

BACKGROUND: In multiple sclerosis (MS), disturbance of the plasminogen activation system (PAS) and blood brain barrier (BBB) disruption are physiopathological processes that might lead to an abnormal fibrin(ogen) extravasation into the parenchyma. Fibrin(ogen) deposits, usually degraded by the PAS, promote an autoimmune response and subsequent demyelination. However, the PAS disruption is not well understood and not fully characterized in this disorder. METHODS: Here, we characterized the expression of PAS actors during different stages of two mouse models of MS (experimental autoimmune encephalomyelitis-EAE), in the central nervous system (CNS) by quantitative RT-PCR, immunohistofluorescence and fluorescent in situ hybridization (FISH). Thanks to constitutive PAI-1 knockout mice (PAI-1 KO) and an immunotherapy using a blocking PAI-1 antibody, we evaluated the role of PAI-1 in EAE models and its impact on physiopathological processes such as fibrin(ogen) deposits, lymphocyte infiltration and demyelination. RESULTS: We report a striking overexpression of PAI-1 in reactive astrocytes during symptomatic phases, in two EAE mouse models of MS. This increase is concomitant with lymphocyte infiltration and fibrin(ogen) deposits in CNS parenchyma. By genetic invalidation of PAI-1 in mice and immunotherapy using a blocking PAI-1 antibody, we demonstrate that abolition of PAI-1 reduces the severity of EAE and occurrence of relapses in two EAE models. These benefits are correlated with a decrease in fibrin(ogen) deposits, infiltration of T4 lymphocytes, reactive astrogliosis, demyelination and axonal damage. CONCLUSION: These results demonstrate that a deleterious overexpression of PAI-1 by reactive astrocytes leads to intra-parenchymal dysfibrinolysis in MS models and anti-PAI-1 strategies could be a new therapeutic perspective for MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Inhibidor 1 de Activador Plasminogénico , Animales , Astrocitos/metabolismo , Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Fibrina , Hibridación Fluorescente in Situ , Ratones , Ratones Noqueados , Esclerosis Múltiple/genética , Inhibidor 1 de Activador Plasminogénico/genética , Serpina E2
3.
Nat Commun ; 15(1): 5070, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38871729

RESUMEN

In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi. In a mouse model of thromboembolic ischemic stroke, our findings demonstrate that the PHySIOMIC generate a distinct hypointense signal on T2*-weighted MRI in the presence of microthrombi, that correlates with the lesion areas observed 24 hours post-stroke. Our microfluidic studies reveal the role of fibrinogen in the protein corona for the thrombosis targeting properties. Finally, we observe the biodegradation and biocompatibility of these particles. This work demonstrates that the PHySIOMIC particles offer an innovative and valuable tool for non-invasive in vivo diagnosis and monitoring of microthrombi, using MRI during ischemic stroke.


Asunto(s)
Medios de Contraste , Modelos Animales de Enfermedad , Compuestos Férricos , Indoles , Imagen por Resonancia Magnética , Polímeros , Trombosis , Animales , Polímeros/química , Imagen por Resonancia Magnética/métodos , Indoles/química , Ratones , Medios de Contraste/química , Compuestos Férricos/química , Trombosis/diagnóstico por imagen , Masculino , Accidente Cerebrovascular/diagnóstico por imagen , Humanos , Fibrinógeno/metabolismo , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Ratones Endogámicos C57BL , Corona de Proteínas/química , Corona de Proteínas/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología
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