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

PLoS Pathogens

Marcelo de Campos Nebel¹  Martín A. Isturiz²  Pablo Schierloh²  Gabriela C. Fernández²  Verónica I. Landoni²  María J. Lapponi³  Cecilia Calatayud⁴ 

[1] Departamento de Genética, CONICET, Ciudad Autónoma de Buenos Aires, Argentina;Departamento de Inmunología, CONICET, Ciudad Autónoma de Buenos Aires, Argentina;Laboratorio de Trombosis Experimental of Instituto de Medicina Experimental (IMEX), CONICET, Ciudad Autónoma de Buenos Aires, Argentina;Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina

关键词: Platelets;    Hemolytic-uremic syndrome;    Inflammation;    Platelet activation;    Cytotoxicity;    Endothelium;    Toxicity;    Toxins;   

DOI  :  10.1371/journal.ppat.1002632

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY