Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha

Abstract

Hemolytic-uremic syndrome (HUS) is generally caused by Shiga toxin (Stx)-producingThe epidemic form of hemolytic-uremic syndrome (HUS) has been associated with enterohemorrhagic infections caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) organisms (33). HUS is the most common cause of acute renal failure in children and is related to the endothelial damage of glomeruli and/or arterioles of the kidney and epithelial cell damage induced by Stx through the interaction with its globotriaosylceramide (Gb 3 ) receptor (35). Although Stx is the main pathogenic factor and is necessary for epidemic HUS development, clinical and experimental evidence suggests that the inflammatory response is able to potentiate Stx toxicity. In fact, both bacterial lipopolysaccharide (LPS) and polymorphonuclear neutrophils (PMN) play a key role in the full development of HUS (15). Moreover, PMN leukocytosis in patients correlates with a poor prognosis (17).Endothelial cell damage is not limited to the kidney but extends to other organs; in severe cases, the brain can be affected. In fact, central nervous system (CNS) complications indicate severe HUS, and brain damage involvement is the most common cause of death (14).However, the pathogenesis of CNS impairment is not yet fully understood. Although it has been demonstrated that human brain endothelial cells (BECs) are relatively resistant to Stx, inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣), markedly increase human BEC sensitivity to Stx cytotoxicity (11).BECs are part of the blood-brain barrier (BBB), which protects the brain from potentially harmful substances and leukocytes present in the bloodstream. Thus, the integrity of BBB function is theorized to be a key component in CNS-associated pathologies, and BEC damage is thought to be one of the possible mechanisms involved in the disruption of the BBB in HUS. In fact, LPS from bacterial infections leads to the release of TNF-␣, interleukin-1␤ (IL-1␤), and reactive oxygen species (ROS), all of which have the ability to open the BBB.Several in vivo studies demonstrated previously that Stx is able to impair BBB function, increasing its permeability (21). Moreover, Stx itself is able to cross the endothelial barrier and enter into the CNS, since Stx activity in cerebrospinal fluid was previously observed (19,23), and Stx was previously immunodetected in many brain cells including astrocytes (ASTs) and neurons (44).

Intraperitoneal administration of Shiga toxin 2 induced neuronal alterations and reduced the expression levels of aquaporin 1 and aquaporin 4 in rat brain

“…The rise on GFAP reactivity, found in the brain of rats i.p. inoculated with sStx2, is consistent with other works in which a direct cytotoxic effect of the toxin was evaluated [17,45,50]. Astrocytes are involved in inflammatory processes, being activated in response to brain injury.…”

“…However, we have also found an increase in GFAP reactivity in periventricular astrocytes of sStx2 injected animals. Stx is able to stimulate significant cytokines release from astrocytes and other cell types [44,45]. Smith et al [44], demonstrated that Stx1 induced a ribotoxic stress response in the intestinal epithelial cell line HCT-8, and activated p38 and JNK mitogen-activated protein kinases, resulting in the stimulation of both chemokine expression and apoptosis.…”

“…Stx and bacterial LPS has been shown to stimulate production of pro-inflammatory cytokines by several cell types, including brain microvascular endothelial cells and astrocytes [45,53,54]. It was reported that Stx1 induced an early inflammatory response in lipopolysaccharide (LPS)-sensitized astrocytes, whereas astrocytes activation and cell death was induced later [45].…”

Enterohemorrhagic Escherichia coli O157:H7 Shiga Toxins Inhibit Gamma Interferon-Mediated Cellular Activation

“…While EHEC produces an array of virulence factors that aid in infection, such as lipopolysaccharide (30) and flagella (4), one of the virulence factors classically associated with EHEC infection is (16,29). Another EHEC virulence factor is its pathogenicity island-encoded type three secretion system (T3SS), which allows the bacterium to disrupt host processes by injecting protein effectors directly into the host cell (46).…”

Toll-like receptor 4 expression on circulating leucocytes in hemolytic uremic syndrome

“…Although Stx is the main pathogenic factor and is necessary for epidemic HUS development, experimental and clinical evidence suggests that the inflammatory response potentiates Stx toxicity. In fact, both bacterial lipopolysaccharide (LPS) and polymorphonuclear neutrophils play a key role in the full development of HUS [5,6]. Therefore, synergism between LPS and Stx2 has been demonstrated as a consequence of the enhancement of Stx2 renal toxicity [7].…”