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

Abstract

Background: Neutrophil extracellular traps (NETs) can stimulate thrombosis, and their degradation is decreased in several autoimmune disorders. It was recently reported that some patients with haemolytic uraemic syndrome (HUS) also fail to degrade NETs and that neutrophils from Shiga toxin-associated HUS are primed to form NETs. Method: We used a well-characterized cohort of 74 thrombotic microangiopathy (TMA) patients, with a subset also providing follow-up samples, and 112 age-matched controls to investigate NET degradation and serum nuclease activity in TMA before, during and after treatment. Results: We identified that in the cohort of TMA patients, 50% of patients with Shiga toxin-associated HUS displayed a decreased ability to degrade NETs. NET degradation correlated with serum nuclease activity, but not with autoantibodies against double-stranded DNA, which has been previously observed in some autoimmune disorders. Further, NET degradation negatively correlated with serum creatinine levels, suggesting that kidney function was negatively impacted by the low NET degradation ability. Conclusions: We revealed that decreased NET degradation is a common feature of Shiga toxin-associated HUS and that it is associated with decreased kidney function in these patients. It remains to be clarified whether improving NET degradation would be beneficial for the patient.

Verotoxin Receptor-Based Pathology and Therapies

“…Other work, however, concluded VT does not bind human neutrophils (Flagler et al, 2007;Geelen et al, 2007), although mouse neutrophils were bound (Fernandez et al, 2000(Fernandez et al, , 2006 and can target mouse kidney (Roche et al, 2007). Nevertheless, recent studies show neutrophil released traps [NETs -anti infectious/inflammatory response (Boeltz et al, 2019)] are increased (Ramos et al, 2016) and their degradation reduced (Leffler et al, 2017) in eHUS.…”

Going Fishing

“…Moreover, NETs can promote immunothrombotic processes since they activate the coagulation system [4]. This said, there is also a growing number of publications reporting that overwhelming NET formation can contribute to a plethora of pathological processes [5,6]. A discussion has therefore arisen as to whether NETs can act as a double-edged sword.…”

The Balancing Act of Inflammation

“…Neutrophils exert several host defense functions, and formation of neutrophil extracellular traps has caught widespread attention in recent years. These were initially recognized as a beneficial part of the innate host response but were, with time, also assigned detrimental roles during prolonged inflammation and sepsis [10-12]. Upon the various forms of cell death that occurs during inflammation, including formation of neutrophil extracellular traps, histones are released to the extracellular environment.…”