GEF-H1 is necessary for neutrophil shear stress–induced migration during inflammation

Fine, Noah; Dimitriou, Ioannis D.; Rullo, Jacob; Sandí, María José; Petri, Bjӧrn; Haitsma, Jack J.; Ibrahim, Hisham M.; Rose, José La; Glogauer, Michael; Kubes, Paul; Cybulsky, Myron I.; Rottapel, Robert

doi:10.1083/jcb.201603109

Cited by 37 publications

(35 citation statements)

References 53 publications

(75 reference statements)

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“…Although neutrophils are professional antimicrobial cells that are supposed to protect the organism against bacteria, their massive recruitment into tissues during sepsis harms the host. In line with this, Fine et al (2016) found that inhibiting septic leukocyte infiltration by neutrophil-specific GEF-H1 deletion increased mouse survival.…”

supporting

confidence: 54%

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Neutrophil mechanotransduction: A GEF to sense fluid shear stress

Niethammer

2016

Journal of Cell Biology

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supporting

confidence: 54%

“… Fine et al (2016) noticed decreased neutrophil infiltration into the peritoneum of GEF-H1 −/− mice after inducing sterile peritonitis by thioglycolate injection. A similar neutrophil recruitment defect was seen after inducing sepsis by puncture of the mouse gut.…”

mentioning

confidence: 88%

Neutrophil mechanotransduction: A GEF to sense fluid shear stress

Niethammer

2016

Journal of Cell Biology

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“…Wild-type and Vav1-deficient neutrophils show the same migratory behavior under static conditions, highlighting that Vav1 is critical for shear-induced perpendicular crawling. Recently, Fine et al [57] further unraveled the underlying mechanism of shear stress-induced migration, specifically the role of the RhoA-specific GEF-H1 during neutrophil recruitment (Fig. 1A).…”

Section: Molecular Mechanismsmentioning

confidence: 98%

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

Begandt

Thome

Sperandio

et al. 2017

Journal of Leukocyte Biology

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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.

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“…In slow migrating cells such as mesenchymal cells, MTs predominately radiate toward the leading edge, and the nucleus toward the cell rear . In these cells, MTs contribute directly to the protrusive forces, whereas in leukocytes, MTs indirectly affect actomyosin directed motility by controlling Rho GTPase activities …”

Section: Introductionmentioning

confidence: 99%

Chemokine-triggered microtubule polymerization promotes neutrophil chemotaxis and invasion but not transendothelial migration

Yadav

Stojkov

Feigelson

et al. 2019

Journal of Leukocyte Biology

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Microtubules (MTs) are critically involved in the transport of material within cells, but their roles in chemotactic leukocyte motility and effector functions are still obscure. Resting neutrophils contain few MTs assembled in an MT organizing center (MTOC) behind their multilobular nuclei. Using a probe of real‐time tubulin polymerization, SiR‐tubulin, we found that neutrophils elongated their MTs within minutes in response to signals from the two prototypic chemotactic peptides, CXCL1 and fMLP. Taxol, a beta‐tubulin binding and MT stabilizing drug, was found to abolish this CXCL1‐ and fMLP‐stimulated MT polymerization. Nevertheless, taxol treatment as well as disruption of existing and de novo generated MTs did not impair neutrophil protrusion and squeezing through IL‐1β‐stimulated endothelial monolayers mediated by endothelial deposited CXCL1 and neutrophil CXCR2. Notably, CXCL1‐dependent neutrophil TEM was not associated with neutrophil MT polymerization. Chemokinetic neutrophil motility on immobilized CXCL1 was also not associated with MT polymerization, and taxol treatment did not interfere with this motility. Nevertheless, and consistent with its ability to suppress MT polymerization induced by soluble CXCL1 and fMLP, taxol treatment inhibited neutrophil chemotaxis toward both chemotactic peptides. Taxol treatment also suppressed CXCL1‐ and fMLP‐triggered elastase‐dependent neutrophil invasion through collagen I barriers. Collectively, our results highlight de novo chemoattractant‐triggered MT polymerization as key for neutrophil chemotaxis and elastase‐dependent invasion but not for chemotactic neutrophil crossing of inflamed endothelial barriers.

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GEF-H1 is necessary for neutrophil shear stress–induced migration during inflammation

Abstract: In their work, Fine et al. demonstrate that GEF-H1 is required for the spreading and crawling of neutrophils in response to intravascular blood flow. They uncover a novel mechanism that couples shear stress with Rho-dependent migratory behavior of neutrophils during inflammation.

Cited by 37 publications

References 53 publications

Neutrophil mechanotransduction: A GEF to sense fluid shear stress

Neutrophil mechanotransduction: A GEF to sense fluid shear stress

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

Chemokine-triggered microtubule polymerization promotes neutrophil chemotaxis and invasion but not transendothelial migration

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