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Séminaire - Emmanuel PinteauxCerebrovascular inflammation and repair of the blood-brain barrier after stroke

Abstract :

Inflammation is a key host defence response that contributes to brain damage after ischemic injury, and is associated with poor outcome in stroke patients. Understanding the mechanisms of inflammation is critical for the development of new therapeutic approaches, and is a clinical priority. The inflammatory response after stroke occurs primarily at the blood-brain barrier (BBB), and cerebrovascular inflammation is driven by the cytokine interleukin-1 (IL-1), the action of which leads to a rapid degradation of the extracellular matrix (ECM) of the BBB, activation of endothelial cells and subsequent infiltration of circulating neurotoxic neutrophils into the brain. We have recently demonstrated that this mechanism of cerebrovascular inflammation occurs locally, but also in distant
areas from the ischemic core leading to delayed neurodegeneration. We have found that ECM remodelling at the cerebrovasculature induces the generation of bioactive ECM fragments that are key regulators of IL-1-induced endothelial cell activation after cerebral ischaemia. ECM remodelling is regulated by the acute phase protein pentraxin-3 (PTX3), the expression of which is dependent on IL-1 in the injured brain, and we have found that PTX3 is a key mediator of brain repair mechanisms including astrogliosis, BBB repair, brain oedema resolution, angiogenesis and neurogenesis. This presentation will highlight these new mechanisms of neurotoxicity and brain tissue repair that could be targeted for the therapeutic treatment of ischemic stroke.

Scientific focus :

After completing a PhD on glial cell responses to oxidative stress in the context of ischemic stroke (Louis Pasteur University, Strasbourg, France), I started a postdoctoral fellowship in the laboratory of Professor Nancy Rothwell, at The University of Manchester (UK), where I studied the neurotoxic actions of the pro-inflammatory cytokine IL-1 in acute neuroinflammation. I was appointed as Lecturer in July 2007 and Senior Lecturer in June 2013. My key research focus is to understand how inflammation driven by IL-1 and extracellular matrix (ECM) degradation contributes to neuronal injury, and to understand how delayed central inflammation interacts with peripheral immunity to promote ECM remodelling, blood-brain barrier repair, neurogenesis and angiogenesis. Our research group has published 42 primary research articles (H-factor = 21). Keys findings are: i) IL-1 acts on astrocytes to release IL-6 and matrix metalloproteinase-9 (MMP9), leading to neuronal cell death, ii) The neuroprotective actions of cannabinoids are mediated by the endogenous IL-1 receptor antagonist in the brain, iii) Neurones are a key target of IL-1 and contribute to the inflammatory response by producing IL-6 and various chemokines, iv) The ECM is a key regulator of IL-1 expression and action in glial cells, v) IL-1 drives pentraxin-3 expression in the brain to promote brain repair. Our research has attracted substantial research funding from the Medical Research Council, UK, FP7-EU, British Heart foundation, the Stroke Association, the Swedish Research Council and the National Health Institute (NIH, USA) (total £2M).