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

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.

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

“…Also, factors released by LPS-and/or Shiga toxin 1-treated astrocytes increased transendothelial permeability in human umbilical vein ECs by reducing TJ proteins expression. 14 Importantly, these authors also showed that NF-κB inhibition or TNF-α blockade inhibited the effects of ACM.…”

“…Moreover, astrocytes modulate endothelial responses under pathologic conditions by secreting factors that cause BBB leakage. 8,14 It is noteworthy the involvement of TNF-α in BBB dysfunction, [15][16][17] as well as in promoting the passage 1 Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 2 of circulating leukocytes into the brain. 18 Despite knowing that METH may induce BBB impairment and neuroinflammation, the possible involvement of pro-inflammatory cytokines in METHinduced BBB alterations has never been investigated.…”

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…In Shiga toxin-producing E. coli associated with hemolytic-uremic syndrome and CNS involvement, both Shiga toxin 1 and Shiga toxin 2 induce cytotoxic effects that lead to a decrease in BBB integrity and to cellular injury in vivo and in vitro (242)(243)(244)(245). LPS may mediate these effects (242,245).…”

Glial Cell–Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome–Dependent IL-1β Production

“…TNF-a and IL-1b have been shown to be major inducers of brain endothelium activation and responsible for the increase in endothelial permeability of the BBB (29)(30)(31). Because both cytokines are produced upon infection of astrocytes and microglia with B. abortus (10), we decided to investigate their role in the activation of HBMEC by Brucella-infected glial cells by first focusing on IL1-b.…”