The Functional State of Neutrophils Correlates With the Severity of Renal Dysfunction in Children With Hemolytic Uremic Syndrome

Fernández, Gabriela; Gómez, Sonia; Ramos, María Victoria Carballo Calero; Bentancor, Leticia V.; Fernández-Brando, Romina Jimena; Landoni, Verónica Inés; López, Laura; Ramirez, Flavia; Diaz, Mario; Alduncín, Marta; Grimoldi, Irene; Exeni, Ramón; Isturiz, Martı́n A.; Palermo, Marina S.

doi:10.1203/01.pdr.0000250037.47169.55

Cited by 32 publications

(40 citation statements)

References 42 publications

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“…Furthermore, the degree of renal impairment has been correlated with the level of activation of circulating PMN [5,29]. Our findings indicating that PMN from HUS patients are able to undergo spontaneous NETosis and the proinflammatory capacity of NET on HGEC are in line with these findings.…”

Section: Discussionsupporting

confidence: 86%

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

et al. 2016

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Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS.

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Section: Discussionsupporting

confidence: 86%

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

et al. 2016

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“…They can rapidly infiltrate the injured brain parenchyma and release proteases and potentially toxic substances (3). For HUS patients, a high peripheral PMN count at presentation was associated largely with a poor prognosis (17). Previous reports established that several chemokines and chemokine receptors are expressed in astroglial cells, either constitutively or induced by inflammatory mediators.…”

Section: Vol 78 2010 Stx1-induced Effects On Lps-sensitized Astrocymentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Landoni

Campos-Nebel

Schierloh³

et al. 2010

Infect Immun

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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).

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“…Neutrophils too are involved in HUS because, in patients, these leukocytes are found to be activated, degranulated, and hyporesponsive to other stimuli (30,31). Moreover, neutrophilia is a typical finding in patients with HUS, and elevated neutrophil counts are considered a poor prognostic factor (32)(33)(34).…”

mentioning

confidence: 99%

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

Brigotti

Carnicelli

Arfilli

et al. 2013

The Journal of Immunology

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Hemolytic uremic syndrome (HUS) caused by intestinal Shiga toxin–producing Escherichia coli infections is a worldwide health problem, as dramatically exemplified by the German outbreak occurred in summer 2011 and by a constant burden of cases in children. Shiga toxins (Stx) play a pivotal role in HUS by triggering endothelial damage in kidney and brain through globotriaosylceramide (Gb3Cer) receptor targeting. Moreover, Stx interact with human neutrophils, as experimentally demonstrated in vitro and as observed in patients with HUS. A neutrophil-protective role on endothelial damage (sequestration of circulating toxins) and a causative role in toxin delivery from the gut to the kidney (piggyback transport) have been suggested in different studies. However, the receptor that recognizes Stx in human neutrophils, which do not express Gb3Cer, has not been identified. In this study, by competition and functional experiments with appropriate agonists and antagonists (LPS, anti-TLR4 Abs, respectively), we have identified TLR4 as the receptor that specifically recognizes Stx1 and Stx2 in human neutrophils. Accordingly, these treatments displaced both toxin variants from neutrophils and, upon challenge with Stx1 or Stx2, neutrophils displayed the same pattern of cytokine expression as in response to LPS (assessed by quantitative RT-PCR, ELISA, or multiplexed Luminex-based immunoassays). Moreover, data were supported by adequate controls excluding any potential interference of contaminating LPS in Stx-binding and activation of neutrophils. The identification of the Stx-receptor on neutrophils provides additional elements to foster the understanding of the pathophysiology of HUS and could have an important effect on the development of therapeutic strategies.

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The Functional State of Neutrophils Correlates With the Severity of Renal Dysfunction in Children With Hemolytic Uremic Syndrome

Cited by 32 publications

References 42 publications

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

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

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils

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