Candice Chapouly will present a seminar entitled: The ambivalent response of reactive astrocytes to BBB breakdown.
A wealth of literature has recently enabled a change in the vision of the Blood Brain Barrier (BBB) structure and integrity which has expanded to include contributions from all components of the neurovascular unit, among which endothelial cells, pericytes, microglia and astrocyte endfeet (Glia Limitans). Specifically, while it is now established that BBB breakdown leads to inflammatory infiltration into the perivascular space during neuropathology, the role of astrocytes from the Glia Limitans appears trickier. Indeed, our group identified reactive astrocytes as key drivers of BBB opening under inflammatory conditions via production of VEGFA and TYMP which down regulate the endothelial tight junction proteins that seal the BBB in the healthy brain. On the other hand we also showed that astrocytes can act as a protective barrier induced by endothelial signals. Once the BBB is open, this secondary barrier takes over to limit the access to the parenchyma via the expression of tight junctions with the same pattern as the digestive epithelium. More recently, we identified delta-like 4 (Dll4) as highly expressed by reactive astrocytes. Dll4 is primarily known to play a role in the regulation of angiogenesis via the Dll4-mediated Notch signaling which is a key pathway for vascular development. However our work highlighted a novel role for Dll4 at the Glia Limitans in controlling astrocytic reactivity and subsequent BBB destabilization during neuropathology. Altogether these findings depict reactive astrocytes, as “Dr Jekyll and Mister Hyde” cells, having complex roles in both recruiting and restricting neuro-inflammatory infiltration. Therefore reactive astrocyte behavior must be determined by taking into account the context and signaling events that vary with the nature and severity of Central Nervous System insults.
