Unraveling novel crosstalk between distinct neutrophil subsets and soluble plasma factors in sepsis and ARDS

Abstract Sepsis is a life-threatening condition caused by an aberrant immune response to infection and subsequent organ dysfunction. Further, due to shared mechanisms such as severe inflammation and endothelial dysfunction, sepsis remains the most common etiology in acute respiratory distress syndrome (ARDS) patients. Despite multiple efforts to identify a distinct signature to support the development of new therapeutics, sepsis remains a significant unmet clinical need. While singular components of the dysregulated immune response have been explored, studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and related changes in soluble plasma factors in sepsis versus healthy donors. Results from our studies identify differentially expressed mature and immature neutrophil subsets in sepsis patients. Further, we show that expression of neutrophil CD10 is associated with factors such as pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in the sepsis cohort. These findings detail a novel correlation between increased presence of immature neutrophils and endothelial dysfunction/metabolic alterations in sepsis patients. Additionally, we profiled the neutrophil landscape and evaluated levels of soluble plasma factors, in a subset of ARDS patients and healthy donors. Here, we present distinct findings that reveal a novel crosstalk between neutrophil subsets and parameters indicative of endothelial dysfunction, in sepsis and ARDS patients. Overall, our study reinforces the importance of data integration and provides novel insights that could help inform future mechanistic studies, early patient stratification and treatment options.