ABSTRACT
In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.
Subject(s)
Astrocytes/metabolism , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Thymidine Phosphorylase/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Blood-Brain Barrier/physiopathology , Cells, Cultured , Cerebral Cortex/drug effects , Deoxyribose/physiology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Endothelium, Vascular/metabolism , Humans , Interleukin-1beta/pharmacology , Mice , Mice, Transgenic , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Multiple Sclerosis/physiopathology , Thymidine Phosphorylase/antagonists & inhibitors , Thymidine Phosphorylase/pharmacology , Transcriptional Activation/drug effects , Transcriptional Activation/physiology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
Geospatial methods were used to study the associations of the environmental thermal-hydrological regime with leprosy prevalence in the Oromia and Amhara regions of Ethiopia. Prediction models were developed that indicated leprosy prevalence was related to: (i) long-term normal climate grid data on temperature and moisture balance (rain/potential evapo-transpiration); (ii) satellite surveillance data on the Normalized Difference Vegetation Index (NDVI) and daytime earth surface temperature (Tmax) from the Advanced Very High Resolution Radiometer (AVHRR); and (iii) a Genetic Algorithm Rule-Set Prediction (GARP) model based on NDVI and Tmax data in relation to leprosy prevalence data. Our results suggest that vertical transmission is not the only means of acquiring leprosy and support earlier reports that a major factor that governs transmission of leprosy is the viability of Mycobacterium leprae outside the human body which is related to the thermal-hydrologic regime of the environment.
