Neutrophil mechanotransduction: A GEF to sense fluid shear stress

Niethammer, Philipp

doi:10.1083/jcb.201609101

Cited by 7 publications

(13 citation statements)

References 15 publications

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“…Dixit et al (23) hypothesized that shear forces used high-affinity LFA-1 transmission to facilitate the cooperation with the calcium release-activated channel Orai1 in directing localized cytoskeletal activation and subsequent directed migration. Besides, Artemenko et al 35 or Niethammer (44,48) have shown that flow could activate internal signalling networks common with chemotaxis. These works support therefore the hypothesis that leukocyte flow guiding may be mediated by active signal transduction and processing, like for chemotaxis, but the mechanistic link between mechanotransduction and mechanotaxis is not fully established.…”

Section: Discussionmentioning

confidence: 99%

A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes

Hornung

Sbarrato

Garcia-Seyda

et al. 2020

Biophysical Journal

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Recruitment of leukocytes from blood vessels to inflamed zones is guided by biochemical and mechanical stimuli, with mechanisms only partially deciphered. Here, we studied the guidance by flow of primary human effector T lymphocytes crawling on substrates coated with ligands of integrins LFA-1 (L2) and VLA-4 (41). We reveal that cells segregate in two populations of opposite orientation for combined adhesion, and show that decisions of orientation rely on a bistable mechanism between LFA-1-mediated upstream and VLA-4-mediated downstream phenotypes. At the molecular level, bistability results from a differential front-rear polarization of both integrins affinity, combined with an inhibiting crosstalk of LFA-1 towards VLA-4. At the cellular level, direction is determined by the passive, flow-mediated orientation of the non-adherent cell parts, the rear uropod for upstream migration and the front lamellipod for downstream migration. This chain of logical events provides a comprehensive mechanism of guiding, from stimuli to cell orientation. STATEMENT OF SIGNIFICANCECell guidance is crucial to many biological functions, but the precise mechanisms remain unclear. We have analyzed here an original phenotype of flow-guided cells mimicking leukocytes crawling onto blood vessels, and show that the controlling parameter of cells decision to migrate upstream or downstream is the relative number of two specific adhesion molecules, the integrins LFA-1 and VLA-4.The spatial polarization of these integrins affinity plus a feedback loop between them creates a bistable system, where cells adhere either by their front or their tail to orient upstream or downstream, respectively. This mechanism proposes a complete chain of events from stimuli to cell orientation which differs strongly from the chemotaxis paradigm, because the external stimuli triggers no signaling.

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Section: Discussionmentioning

confidence: 99%

A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes

Hornung

Sbarrato

Garcia-Seyda

et al. 2020

Biophysical Journal

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“…Brief exposure to high shear sensitizes platelets to activation under subsequent low insult shear, so it is reasonable to presume leukocytes might be affected the same way ( 36 ). It has been suggested that shear stress activates leukocytes through structural changes rather than ligand-induced signal transduction ( 37 ). Interestingly, repeated mechanical deformation at 25 dynes/cm 2 of primed neutrophils can return them to a resting state ( 38 ), but above this leads to structural disruption ( 39 ).…”

Section: Inflammation In Response To Ventricular Assist Devicesmentioning

confidence: 99%

The Inflammatory Response to Ventricular Assist Devices

et al. 2018

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The therapeutic use of ventricular assist devices (VADs) for end-stage heart failure (HF) patients who are ineligible for transplant has increased steadily in the last decade. In parallel, improvements in VAD design have reduced device size, cost, and device-related complications. These complications include infection and thrombosis which share underpinning contribution from the inflammatory response and remain common risks from VAD implantation. An added and underappreciated difficulty in designing a VAD that supports heart function and aids the repair of damaged myocardium is that different types of HF are accompanied by different inflammatory profiles that can affect the response to the implanted device. Circulating inflammatory markers and changes in leukocyte phenotypes receive much attention as biomarkers for mortality and disease progression. However, they are seldom used to monitor progress during and outcomes from VAD therapy or during the design phase for new devices. Even the partial reversal of heart damage associated with heart failure is a desirable outcome from VAD use. Therefore, improved understanding of the interplay between VADs and the recipient's inflammatory response would potentially increase their uptake, improve patient lives, and fuel research related to other blood-contacting medical devices. Here we provide a review of what is currently known about inflammation in heart failure and how this inflammatory profile is altered in heart failure patients receiving VAD therapy.

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“…Shear stress affects neutrophils independently of biomaterials as evidenced by increased activation of granulocytes in HMII patients compared to the HVAD (35). It is suggested that the physical forces of non-physiological shear stress cause structural changes that activate granulocytes (65). Activation is marked by an increase in MAC-1 expression as observed in the HMII patients (35).…”

Section: Resultsmentioning

confidence: 95%

“…GEF-H1 is activated in response to shear stress to promote spreading, crawling, and transmigration of neutrophils (61). Depolymerised GEF-H1 re-localises to the uropod to stimulate Rho signalling resulting in intracellular tension and cellular contractility (65).…”

Section: Innate Immune Cellsmentioning

confidence: 99%

“…The development of new test devices that allow modifications of gap size, residence time, shear stress, biomaterial types, and surface finish for leukocyte analysis in vitro would prove highly 57↑LMPs (54,58) ↑WBC trauma compared to RBC in rotary blood pumps (56) ↑Disrupted WBC morphology with increasing shear (48,49) Normal leukocyte count throughout (36) ↑Proinflammatory cytokines (21, 22) ↑Complement activation (22) ↓WBC co range (35 ↑LMPs ( Neutrophils ↑Activated LMPs (38) ↑Elastase levels (57) ↓Phagocytosis with high shear (52) ↑Depolarisation of neutrophils with increasing shear (64,68) Minimum level of shear stress for neutrophil deactivation (62) GEF-H1 (61,65) ↑Cell swelling, increased random granule velocity, and reduced cell stiffness with increasing shear (53) ↑Neutrophil-platelet aggregates (40) ↑Elastase levels (22) ↑Granul…”

Section: Future Outlookmentioning

confidence: 99%

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Mechanical shear stress and leukocyte phenotype and function: Implications for ventricular assist device development and use

et al. 2018

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Heart failure (HF) remains a disease of ever increasing prevalence in the modern world. Patients with end-stage HF are being referred increasingly for mechanical circulatory support (MCS). MCS can assist patients who are ineligible for transplant and stabilise eligible patients prior to transplantation. It is also used during cardiopulmonary bypass (CPB) surgery to maintain circulation whilst operating on the heart. Whilst MCS can stabilise HF and improve quality of life, complications such as infection and thrombosis remain a common risk. Leukocytes can contribute to both of these complications. Contact with foreign surfaces and the introduction of artificial mechanical shear stress can lead to activation of leukocytes, reduced functionality, and the release of pro-inflammatory and pro-thrombogenic microparticles. Assessing the impact of mechanical trauma to leukocytes is largely overlooked in comparison to red blood cells and platelets. This review provides an overview of the available literature on the effects of in vitro to clinical MCS systems on leukocyte phenotype and function. One purpose of this review is to emphasise the importance of studying mechanical trauma to leukocytes to better understand the occurrence of adverse events during MCS.

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Neutrophil mechanotransduction: A GEF to sense fluid shear stress

Abstract: Philipp Niethammer highlights work from the Rottapel group exploring the role of the GEF-H1 protein in shear- sensing by neutrophils.

Cited by 7 publications

References 15 publications

A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes

A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes

The Inflammatory Response to Ventricular Assist Devices

Mechanical shear stress and leukocyte phenotype and function: Implications for ventricular assist device development and use

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