Dysregulation of Neutrophil-Endothelial Communication in Sepsis: Mechanisms and Therapeutic Perspectives

Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulation in immune response to infection. Dysregulated neutrophil activity plays a critical role in sepsis-induced organ failure through interactions with the vascular endothelial cells during forward and reverse migration, resulting in vascular barrier disruption and increased neutrophil trafficking into vital organs. Therapeutic approaches for treating sepsis are mainly supportive. Due to limited clinical translation from rodent models, complexity of the pathophysiology, and most importantly, the heterogenous nature of sepsis, no significant therapeutics have been successfully developed to address the underlying immune dysregulation. In this review, we will discuss the important gap in knowledge on the fundamental mechanisms of neutrophil-endothelial interaction, the role that neutrophil forward and reverse migration plays in organ damage in sepsis, and how neutrophil and endothelial cell heterogeneity impact cell-cell communication. We will explore emerging methodologies, including novel omic and microphysiological systems, to study the underlying mechanism of neutrophil-endothelial interaction and neutrophil forward migration/reverse migration. Finally, we will review potential therapeutic targets modulating neutrophil-endothelial interaction and the challenges of translating them from bench to bedside.