EFHHBBBMS · Endothelial Hedgehog autocrine signaling at the Blood Brain Barrier controls inflammatory Central Nervous System lesion size and severity through Gas1 co-receptor modulation.

Endothelial Hedgehog autocrine signaling at the Blood Brain Barrier controls inflammatory CentralNervous System lesion size and severity through Gas1 co-receptor modulation.

In a healthy individual, the central nervous system (CNS) parenchyma is protected from the peripheral circulation by the blood–brain barrier (BBB). Importantly, during multiple sclerosis, the abnormal permeability of the BBB allows penetration into the CNS of inflammatory cells and plasmatic proteins which drive lesion formation. Previous studies have identified the Hedgehog (HH) pathway as a regulator of BBB integrity in multiple sclerosis, HIV, and stroke and we showed that desert hedgehog (DHH) is expressed constitutively at the BBB in adults. Interestingly, a wealth of literature has enabled a change in the vision of BBB structure and integrity, which has expanded to include contributions from both barrier properties of the vascular endothelial cells and the astrocytic end feet of the neurovascular unit. While it is now well established that BBB breakdown leads to soluble factor and inflammatory cell infiltration into the CNS during neuropathology, the role of the Glia Limitans is more complex. Indeed, astrocytes, described as reactive, may demonstrate opposing roles in both recruiting and restricting neuroinflammatory infiltration depending on the context. Specifically, in multiple sclerosis, it has been shown that reactive astrocytes, on one hand, produce pro-inflammatory and pro-permeability factors and on the other hand, neuroprotective factors. Astrocyte barrier properties are not as well characterized as those of the BBB. However, several groups have highlighted barrier properties at the Glia Limitans which is also required for immune cell trafficking across the neurovascular unit. Strikingly, our recent work has given considerable attention to a new property of reactive astrocytes: the expression of tight junction proteins, notably Claudin4, under inflammatory conditions. This result provides yet another argument in favor of astrocytic barrier properties.The first objective of our study was to decipher the role of Dhh in maintaining BBB tightness. The second objective was to demonstrate that a double barrier system comprising both the BBB and Glia Limitans is implemented in the CNS and regulated by a crosstalk going from endothelial cell to astrocytes using endothelial Dhh knockdown as a model of permeable BBB.

Data: CORDIS, © European Union