How neutrophils resist shear stress at blood vessel walls: molecular mechanisms, subcellular structures, and cell–cell interactions

Abstract

Neutrophils are the first cells arriving at sites of tissue injury or infection to combat invading pathogens. Successful neutrophil recruitment to sites of inflammation highly depends on specific molecular mechanisms, fine-tuning the received information into signaling pathways and converting them into well-described recruitment steps. This review highlights the impact of vascular flow conditions on neutrophil recruitment and the multitude of mechanisms developed to enable this sophisticated process under wall shear stress conditions. The recruitment process underlies a complex interplay between adhesion and signaling molecules, as well as chemokines, in which neutrophils developed specific mechanisms to travel to sites of lesion in low and high shear stress conditions. Rolling, as the first step in the recruitment process, highly depends on endothelial selectins and their ligands on neutrophils, inducting of intracellular signaling and subsequently activating β integrins, enabling adhesion and postadhesion events. In addition, subcellular structures, such as microvilli, tethers, and slings allow the cell to arrest, even under high wall shear stress. Thereby, microvilli that are pulled out from the cell body form tethers that develop into slings upon their detachment from the substrate. In addition to the above-described primary capture, secondary capture of neutrophils via neutrophil-neutrophil or neutrophil-platelet interaction promotes the process of neutrophil recruitment to sites of lesion. Thus, precise mechanisms based on a complex molecular interplay, subcellular structures, and cell-cell interactions turn the delicate process of neutrophil trafficking during flow into a robust response allowing effective neutrophil accumulation at sites of injury.

A Fundamental Role of Myh9 for Neutrophil Migration in Innate Immunity

“…5I). As the basic properties and phenotypical and functional characteristics of dHoxb8 cells were very similar to freshly isolated murine neutrophils (4,37), we concluded that this model represents a useful tool to study neutrophil trafficking.…”

“…During acute inflammation, neutrophils are the first leukocytes to arrive at the site of injury (1,2). The recruitment of neutrophils from the blood stream into the inflamed tissue follows a consecutive multistep cascade that includes capturing, rolling, firm adhesion, adhesion strengthening, spreading, intraluminal crawling, transmigration, abluminal crawling, and interstitial migration to sites of lesion (3,4).…”

Neutrophil accumulation and NET release contribute to thrombosis in HIT

“…Our finding of enhanced in vitro neutrophil binding parallels the increased adhesion seen in vivo in the setting of our murine model of HIT, with or without endothelial cell injury. We speculate that neutrophil adhesion immediately downstream of growing venular injury may be due to increased turbulent flow around larger thrombi that is known to enhance neutrophil adhesion to the endothelial lining (34). It may also be due to the release of PF4 from activated platelets within the thrombus that results in increased assembly of antigenic complexes on the downstream endothelium, leading to more HIT antibody binding and endothelial activation (11).…”

Calcium signalling and related ion channels in neutrophil recruitment and function

“…Additionally, PMNs ligate immobilized chemokines presented on inflamed endothelial cells, thereby inducing the high‐affinity conformation of β 2 ‐integrins lymphocyte function‐associated antigen‐1 (LFA‐1) and macrophage‐1 antigen (Mac‐1), which leads to firm adhesion of neutrophils on the inflamed endothelium . Postarrest modifications, including β 2 ‐integrin clustering and anchoring to the cytoskeleton, result in neutrophil spreading, adhesion strengthening and intraluminal crawling . Crawling of neutrophils along the inflamed vessel wall is a critical step for their localization at appropriate sites for extravasation (diapedesis).…”

“…6 Postarrest modifications, including b 2 -integrin clustering and anchoring to the cytoskeleton, result in neutrophil spreading, adhesion strengthening and intraluminal crawling. 7 Crawling of neutrophils along the inflamed vessel wall is a critical step for their localization at appropriate sites for extravasation (diapedesis). Similar to the intravascular adhesion steps, emigration of neutrophils into inflamed tissue also proceeds in a cascade-like fashion including transmigration across the endothelial layer into the subendothelial space, followed by penetration of the vascular basement membrane.…”