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

Abstract

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.

Decreased Neutrophil Extracellular Trap Degradation in Shiga Toxin-Associated Haemolytic Uraemic Syndrome

“…These observations in combination with recent reports of a decreased degradation of neutrophil extracellular traps (NETs) in TMA [10] and increased formation of NETs [11] have suggested a role for NETs in thrombotic microangiopathic disorders. NETs consist of decondensed chromatin covered with antimicrobial proteins/peptides and are released from mainly activated neutrophils in a ROS/NADPH-dependent manner [12,13] .…”

“…Globular actin in the presence of ATP can inhibit DNase-I [23] , potentially presenting a mechanism for how tissue damage that releases ATP and actin can prevent NET degradation during infections. It was recently shown that neutrophils from Stx-associated HUS patients are more likely to produce NETs [11] , and it is therefore tempting to speculate that the decreased NET degradation which we observed in STEC-HUS may be part of the acute response to fight the infection. As a consequence, increased NET release in combination with attenuated degradation may adversely contribute to some of the kidney damage in STEC-HUS through STEC-independent mechanisms such as the pro-thrombotic properties of NETs [24] .…”

Intracellular Clearance by Nobel Laureates

“…Along with other NET articles published in the Journal of Innate Immunity [24][25][26] , these studies emphasize the importance of neutrophils and extracellular traps in the early immune response to an invading pathogen. Together with the other contributions in the first 2017 issue, this collection of articles covers a number of essential scientific problems within the field of innate immunity that should be of great interest to our readers.…”

Going Fishing

“…It is more than obvious that this chapter has not yet been closed since many researchers are still contributing to it. It was first believed that NETs play an important role in immobilizing bacterial pathogens, but evidence is now accumulating that they are also involved in many other processes, such as the induction of inflammatory reactions [2,3]. Moreover, NETs can promote immunothrombotic processes since they activate the coagulation system [4].…”