Actin dynamics in the regulation of endothelial barrier functions and neutrophil recruitment during endotoxemia and sepsis

Abstract

Sepsis is a leading cause of death worldwide. Increased vascular permeability is a major hallmark of sepsis. Dynamic alterations in actin fiber formation play an important role in the regulation of endothelial barrier functions and thus vascular permeability. Endothelial integrity requires a delicate balance between the formation of cortical actin filaments that maintain endothelial cell contact stability and the formation of actin stress fibers that generate pulling forces, and thus compromise endothelial cell contact stability. Current research has revealed multiple molecular pathways that regulate actin dynamics and endothelial barrier dysfunction during sepsis. These include intracellular signaling proteins of the small GTPases family (e.g., Rap1, RhoA and Rac1) as well as the molecules that are directly acting on the actomyosin cytoskeleton such as myosin light chain kinase and Rho kinases. Another hallmark of sepsis is an excessive recruitment of neutrophils that also involves changes in the actin cytoskeleton in both endothelial cells and neutrophils. This review focuses on the available evidence about molecules that control actin dynamics and regulate endothelial barrier functions and neutrophil recruitment. We also discuss treatment strategies using pharmaceutical enzyme inhibitors to target excessive vascular permeability and leukocyte recruitment in septic patients.

Keywords: Acute lung injury; Acute respiratory distress syndrome; Adhesion; Diapedesis; Inflammation; Tight junction.

Fig. 1

Signaling pathways regulating endothelial barrier functions during sepsis. Several different effectors can activate receptor-mediated activation of small GTPases that induce actin remodeling. Myosin gets phosphorylated via RhoA/ROCK and MLCK, and interacts with actin filaments to form contractile actomyosin stress fibers. On the other hand, several ABP, such as cortactin, filamin A/B, cofilin and VASP, are getting phosphorylated and translocated to control inflammatory actin dynamics. Several substances have been identified that inhibit these pathways and counteract endothelial hyperpermeability during sepsis (bottom)

Fig. 2

Actin-dependent mechanisms controlling the interactions of neutrophils with endothelial cells under septic conditions. In neutrophils, ROCK gets activated in response to CXCL12 to control actin dynamics that regulate integrin mobility and clustering, and expression of Mac1. In endothelial cells, ROCK-mediated NF-ĸB nuclear translocation induces expression of ICAM-1 to facilitate neutrophil adhesion. ROCK-mediated actin contractility contributes to endothelial junction destabilization and neutrophil transendothelial migration