Figure 2.

Leukocyte adhesion cascade during sepsis: During sepsis, both PAMPs and DAMPs trigger the activation of neutrophils and endothelial cells, prompting the production of cytokines and chemoattractants. Consequently, neutrophils display surface molecules that interact with adhesion molecules expressed by activated endothelium. The initial rolling step involves interactions between E/P-selectin and their ligands, such as PSGL-1, which slows down the neutrophil. Subsequently, firm adhesion is mediated by endothelial adhesion molecules like ICAM-1, ICAM-2, and VCAM-1, interacting with neutrophil ligands, such as β2 integrins. In response to chemoattractants, adhered neutrophils migrate through endothelial junctions, facilitated by PECAM-1, VE-cadherin and JAMs. Concurrently, activated neutrophils release cytokines, reactive oxygen species (ROS), and proteases, or undergo the formation of neutrophil extracellular traps (NETs). During sepsis, the endothelial glycocalyx (eGC) is degraded, endothelial cell tight junctions are damaged, and there is an increase in endothelial cell apoptosis, ultimately leading to compromised barrier function and increased permeability.