Abstract
Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.
Highlights
In a healthy individual, the central nervous system (CNS) parenchyma is protected from the peripheral circulation by the blood–brain barrier (BBB), which tightly regulates the entry and exit of soluble factors and immune cells [1]
While it is well established that BBB breakdown leads to soluble factor and inflammatory cell infiltration into the perivascular space (PVS) during neuropathology, the role of the Glia Limitans is more complex
We demonstrated that Dhh is severely down-regulated at the BBB under inflammatory conditions both in vitro using human brain microvascular endothelial cells (HBMECs) treated with interleukin-1β (IL-1β) (Fig 1C and S1 Data) and in vivo (Fig 1F and S1 Data) using a preclinical model of multiple sclerosis
Summary
The central nervous system (CNS) parenchyma is protected from the peripheral circulation by the blood–brain barrier (BBB), which tightly regulates the entry and exit of soluble factors and immune cells [1]. During multiple sclerosis, the abnormal permeability of the BBB allows penetration into the CNS parenchyma of inflammatory cells and soluble factors such as autoantibodies, cytokines, and toxic plasma proteins, which drive lesion formation and acute disease exacerbation [2,3]. Identifying key mechanisms that promote BBB tightness is currently considered to be a main strategy for controlling leukocyte and humoral entry, preventing acute relapse and disability progression in multiple sclerosis. The interaction of HH proteins with their specific receptor Patched-1 (PTCH1) derepresses the transmembrane protein Smoothened (SMO), which activates downstream pathways including the canonical HH pathway leading to the activation of Gli family zinc finger (Gli) transcription factors, and the so-called noncanonical HH pathways, which are independent of SMO and/or Gli [10]
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