Shiga Toxin 1 Induces on Lipopolysaccharide-Treated Astrocytes the Release of Tumor Necrosis Factor-alpha that Alter Brain-Like Endothelium Integrity

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Abstract
The hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia and renal dysfunction. The typical form of HUS is generally associated with infections by Gram-negative Shiga toxin (Stx)-producing Escherichia coli (STEC). Endothelial dysfunction induced by Stx is central, but bacterial lipopolysaccharide (LPS) and neutrophils (PMN) contribute to the pathophysiology. Although renal failure is characteristic of this syndrome, neurological complications occur in severe cases and is usually associated with death. Impaired blood-brain barrier (BBB) is associated with damage to cerebral endothelial cells (ECs) that comprise the BBB. Astrocytes (ASTs) are inflammatory cells in the brain and determine the BBB function. ASTs are in close proximity to ECs, hence the study of the effects of Stx1 and LPS on ASTs, and the influence of their response on ECs is essential. We have previously demonstrated that Stx1 and LPS induced activation of rat ASTs and the release of inflammatory factors such as TNF-α, nitric oxide and chemokines. Here, we demonstrate that rat ASTs-derived factors alter permeability of ECs with brain properties (HUVECd); suggesting that functional properties of BBB could also be affected. Additionally, these factors activate HUVECd and render them into a proagregant state promoting PMN and platelets adhesion. Moreover, these effects were dependent on ASTs secreted-TNF-α. Stx1 and LPS-induced ASTs response could influence brain ECs integrity and BBB function once Stx and factors associated to the STEC infection reach the brain parenchyma and therefore contribute to the development of the neuropathology observed in HUS. Hemolytic-uremic syndrome (HUS) is generally caused by Shiga toxin (Stx)-producing Escherichia coli but bacterial lipopolysaccharide (LPS) and neutrophils (PMN) contribute to the pathophysiology. Acute renal failure is the main feature of HUS, but in severe cases, patients develop neurological complications, which are usually associated with death. Although the mechanisms of neurological damage remain uncertain, alterations/injury of brain endothelial cells (ECs) which constitute the blood-brain barrier (BBB) is clear. Astrocytes (ASTs) are inflammatory cells enclosing ECs and are responsible of the normal function of the barrier. We have recently demonstrated that Stx1, one of the most common types of Stx, induce an inflammatory response in LPS-treated ASTs. We then study the effects of factors released by ASTs in response to LPS and/or Stx1 on brain-like ECs. We demonstrate that Stx1 induces in LPS-treated ASTs the release of factors that alter brain properties in ECs, including the permeability; turning them more susceptible to Stx1 toxic effects. Furthermore, they activate ECs, neutrophils (PMN) and platelets and render ECs into a proagregant state promoting PMN and platelet adhesion. Our results suggest that ASTs could influence brain ECs integrity and BBB function once Stx in combination with bacterial factors reach the brain parenchyma.

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