Intracellular communication and immunothrombosis in sepsis

Abstract

Inflammation and coagulation are the critical responses to infection that include leukocytes, platelets, and vascular endothelial cells responding in concert to eradicate the invading pathogen. In sepsis, a variety of cell surface receptors, including toll-like receptors, Fcγ-receptors, G-protein-coupled receptors, and adhesion receptors, detect the pathogens and elicit thromboinflammatory responses. Concurrently, the molecular patterns released from host damaged cells accelerate the immune responses through binding to the same pattern recognition receptors. Cytokines, chemokines, and extracellular vesicles are important mediators for amplifying the responses to distant cells as part of the systemic response to infections. At the same time, cells communicate with each other via direct contact, adhesion molecules, paracrine mediators, and tunneling nanotubes, which are important for regulating inflammation and thrombus formation. Despite increasing attention to immunothrombosis in sepsis, these close communication systems are less understood but play a critical role in host defense mechanisms. In this review, cellular activation and direct intercellular communication systems in sepsis with a focus on the coagulation response will be considered.

Keywords: adhesion molecule; endothelial cell; immunothrombosis; platelet; sepsis; thromboinflammation.

FIGURE 1

Microthrombus formation in sepsis. In sepsis, signals transduced through various receptors on the surface of monocytes, neutrophils, and platelets induce the cellular responses of these cells. The representative receptors are toll‐like receptors (TLRs), Fcγ receptor (FcγR), adhesion receptor macrophage‐1 antigen (Mac‐1, complement receptor 3), and protease activated receptor (PAR)‐1. Activated monocytes express tissue factor and phosphatidylserine on the surface, which initiate coagulation cascades. The responses also include the release proinflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin (IL)‐6. Activated neutrophils eject neutrophil extracellular traps (NETs) and release various damage‐associated molecular patterns (DAMPs) along with cell death. Platelets release procoagulant microvesicles and prothrombotic substances such as von Willebrand factor (VWF) and platelet factor 4 (PF4). Blue dashed arrow: proinflammatory reaction; red dashed arrow: prothrombotic reaction; LPS: lipopolysaccharide; Ig: immunoglobulin; GP: glycoprotein; C3b: complement fragment 3b; PAI‐1: plasminogen activator inhibitor 1.

FIGURE 2

Cooperative interplay between cellular adhesion molecules. Interactions between the platelets, platelets and leukocytes, platelets and endothelial cells, and leukocytes and endothelial cells are shown. Interactions occur via direct contact between cell surface adhesion molecules, or via binding to the intermediate substances such as von Willebrand factor and fibrinogen. These interplays are either the result or cause of activation of related cells.

FIGURE 3

Immunothrombus formation in sepsis model. Sepsis model of rat was made by intravenous injection of lipopolysaccharide. Six hours later, micro thrombus formed of leukocyte–platelet aggregates was observed in the mesenteric venule under the intravital microscope (A). The nuclei of the severely damaged endothelial cells where the thrombus was formed were stained by DAPI (B). DNA component in neutrophil extracellular traps (NETs) (white arrows) were visualized by the immunofluorescence (Nuclear‐ID Red stain) (C). Platelets staining by anti‐CD 41 antibody (yellow) was overlayed (D).

FIGURE 4

Tunneling nanotubes. Phase‐contrast view (left) and anti‐CD11b immunofluorescent stain (right) of the tunneling nanotubes. Leukocytes were co‐cultured with Escherichia coli for 4 h. Leukocytes are connected by string‐like tunneling nanotubes. Since the tube is formed of the cytoplasmic membrane, it is stained by anti‐CD 11b antibody.