Regulation of human neutrophil IL-1β secretion induced by Escherichia coli O157:H7 responsible for hemolytic uremic syndrome

Shiga-toxin producing Escherichia coli (STEC) infections can cause from bloody diarrhea to Hemolytic Uremic Syndrome. The STEC intestinal infection triggers an inflammatory response that can facilitate the development of a systemic disease. We report here that neutrophils might contribute to this inflammatory response by secreting Interleukin 1 beta (IL-1β). STEC stimulated neutrophils to release elevated levels of IL-1β through a mechanism that involved the activation of caspase-1 driven by the NLRP3-inflammasome and neutrophil serine proteases (NSPs). Noteworthy, IL-1β secretion was higher at lower multiplicities of infection. This secretory profile modulated by the bacteria:neutrophil ratio, was the consequence of a regulatory mechanism that reduced IL-1β secretion the higher were the levels of activation of both caspase-1 and NSPs, and the production of NADPH oxidase-dependent reactive oxygen species. Finally, we also found that inhibition of NSPs significantly reduced STEC-triggered IL-1β secretion without modulating the ability of neutrophils to kill the bacteria, suggesting NSPs might represent pharmacological targets to be evaluated to limit the STEC-induced intestinal inflammation.Author summary: The enteric pathogen Shiga toxin (Stx)-producing Escherichia coli (STEC) is a food- and water-borne bacteria that upon ingestion colonizes the intestine where it releases Shiga-toxins (Stx) and other virulence factors. STEC not only can cause self-limited gastrointestinal infections and bloody diarrhea but also a severe and potentially deathly systemic condition, known as Hemolytic Uremic Syndrome (HUS). There are no vaccines available to prevent STEC infections or specific treatments. The most frequent clinical STEC isolate in HUS is E. coli O157:H7. Severe inflammation and damage to the mucosal membrane are common symptoms of gastroenteritis induced by STEC. Interleukin-1β (IL-1β) is a highly pro-inflammatory mediator. Neutrophils are professional phagocytes that are extensively recruited to the intestinal mucosa upon STEC infection. Here we determined that human neutrophils secrete IL-1β in response to STEC and identified a molecular mechanism that limits the secretion of this mediator as the dose of bacteria that interacts with the neutrophils increases. Our study provides new insights into the role of neutrophils in the inflammatory response against STEC infections and opens a new road to investigate therapeutic strategies to avoid the progression to HUS.