Amyloid-? and caspase-1 are indicators of sepsis and organ injury

Background Sepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post-discharge. The present study identifies a novel regulatory relationship between amyloid-ss (A ss) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes. Methods Medical ICU patients and healthy individuals were consented for blood and clinical data collection. Plasma cytokine, caspase-1 and A ss levels were measured. Data were compared against indices of multiorgan injury and other clinical parameters. Additionally, recombinant proteins were tested in vitro to examine the effect of caspase-1 on a functional hallmark of A ss, namely aggregation. Results Plasma caspase-1 levels displayed the best predictive value in discriminating ICU patients with sepsis from non-infected ICU patients (area under the receiver operating characteristic curve=0.7080). Plasma caspase-1 and the A ss isoform A ss x-40 showed a significant positive correlation and A ss x-40 associated with organ injury. Additionally, A ss plasma levels continued to rise from time of ICU admission to 7 days postadmission. In silico, A ss harbours a predicted caspase-1 cleavage site, and in vitro studies demonstrated that caspase-1 cleaved A ss to inhibit its auto-aggregation, suggesting a novel regulatory relationship. Conclusions A ss x-40 and caspase-1 are potentially useful early indicators of sepsis and its attendant organ injury. Additionally, A ss x-40 has emerged as a potential culprit in the ensuing development of post-ICU syndrome.