Fluid Stresses on the Membrane of Migrating Leukocytes

Su, Susan S.; Schmid‐Schönbein, Geert W.

doi:10.1007/s10439-007-9406-7

Cited by 18 publications

(31 citation statements)

References 20 publications

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“…2C, t ϭ 1 min micrograph), whereas WKY pseudopods in suspension maintained the characteristic uniform leading edge ( Fig. 2A, t ϭ 0 micrograph) as seen in normal neutrophils (33).…”

Section: Resultsmentioning

confidence: 81%

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Chen

DeLano

Valdez

et al. 2010

American Journal of Physiology-Cell Physiology

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Physiological fluid shear stress evokes pseudopod retraction in normal leukocytes by a mechanism that involves the formyl peptide receptor (FPR) as mechanosensor. In hypertensives, such as the spontaneously hypertensive rat (SHR), leukocytes lack the normal fluid shear response. The increased activity of matrix metalloproteinases (MMPs, including MMP-9) in SHR plasma is associated with cleavage of several cell membrane receptors. We hypothesize that the attenuated fluid shear response in leukocytes (neutrophils) of the SHR is due to extracellular proteolytic cleavage of the FPR. We show that suspended SHR neutrophils in whole blood sheared in a cone-and-plate device or individual neutrophils adherent to a glass surface and subject to fluid shear exhibited reduced pseudopod retractions compared with neutrophils of control Wistar-Kyoto (WKY) rats. SHR neutrophils and naïve Wistar rat neutrophils exposed to SHR plasma also exhibited impaired fluid shear responses as shown by their inability to project pseudopods with fluid shear. Labeling of extracellular FPR revealed that the FPR density in SHR neutrophils is on average 27% reduced compared with those of the WKY rats. Exposure of Wistar rat neutrophils to the gelatinase MMP-9 (final concentration 5 nM) led to attenuation of fluid shear response and decrease in extracellular FPR density. Chronic treatment of the SHR with a broad-acting MMP inhibitor, doxycycline, significantly improved the fluid shear response and increased the FPR extracellular density of SHR neutrophils. These results suggest that proteolytic cleavage of the FPR may interfere with normal fluid shear-induced pseudopod retractions in SHR neutrophils.formyl peptide receptor; pseudopod projection; cone-and-plate device; N-formyl-methionine-leucine-phenylalanine; immunohistochemistry ONE OF THE FEATURES OF LEUKOCYTE stimulation by N-formylMet-Leu-Phe (fMLP) is the projection of pseudopods by Factin polymerization (8,41). In a normal circulation, the majority of leukocytes have few or no pseudopods, an effect mediated by fluid shear stress with retraction of pseudopods (14,26). However, an increased number of circulating leukocytes project pseudopods in the circulation of hypertensives, such as the spontaneously hypertensive rat (SHR), with elevated microvascular resistance (9). The impaired movement of such neutrophils with pseudopods through capillaries causes substantial elevation of hemodynamic resistance in the SHR (9). Currently, the mechanism by which an increased number of pseudopods form on circulating neutrophils of the SHR under normal physiological fluid shear is unexplored.Recently, G protein-coupled receptors, such as the formyl peptide receptor (FPR) in the case of neutrophils, have been shown to serve as mechanosensors for fluid shear stress (21). Exhibiting high constitutive activity, the FPR binding target for N-formyl chemoattractants is predominantly expressed on neutrophils and monocytes (15, 21). Herein we are interested in investigating the fluid shear response of neutrophils of ...

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“…2C, t ϭ 1 min micrograph), whereas WKY pseudopods in suspension maintained the characteristic uniform leading edge ( Fig. 2A, t ϭ 0 micrograph) as seen in normal neutrophils (33).…”

Section: Resultsmentioning

confidence: 81%

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Chen

DeLano

Valdez

et al. 2010

American Journal of Physiology-Cell Physiology

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“…These experimental environments created normal and shear stresses with peak values of ~70 mPa. However, many cell monolayer flow studies are capable of applying shear stresses in the range of 1.0 Pa due to faster flow rates of 14 mm/s [13]. In an exploration of the potential for microfluidic applications of stresses at higher levels as well as the induced cellular strain response, two of the flow conditions were each modeled with 0.1, 1.0, and 10.0 Pa peak stresses: (1) a uniform flow field and (2) an extensional flow scenario (Fig.…”

Section: Methodsmentioning

confidence: 99%

Two-Dimensional Modeling of Nanomechanical Strains in Healthy and Diseased Single-Cells During Microfluidic Stress Applications

Wilson

Kohles

2010

Journal of Nanotechnology in Engineering and Medicine

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Investigations in cellular and molecular engineering have explored the impact of nanotechnology and the potential for monitoring and control of human diseases. In a recent analysis, the dynamic fluid-induced stresses were characterized during microfluidic applications of an instrument with nanometer and picoNewton resolution as developed for single-cell biomechanics (Kohles, S. S., Nève, N., Zimmerman, J. D., and Tretheway, D. C., 2009, "Stress Analysis of Microfluidic Environments Designed for Isolated Biological Cell Investigations," ASME J. Biomech. Eng., 131 (12), p. 121006). The results described the limited stress levels available in laminar, creeping-flow environments, as well as the qualitative cellular strain response to such stress applications. In this study, we present a two-dimensional computational model exploring the physical application of normal and shear stress profiles (with 0.1, 1.0, and 10.0 Pa peak amplitudes) potentially available within uniform and extensional flow states. The corresponding cellular strains and strain patterns were determined within cells modeled with healthy and diseased mechanical properties (5.0-0.1 kPa moduli, respectively). Strain energy density results integrated over the volume of the planar section indicated a strong mechanical sensitivity involving cells with disease-like properties. In addition, ex vivo microfluidic environments creating in vivo stress states would require freestream flow velocities of 2-7 mm/s. Knowledge of the nanomechanical stresses-strains necessary to illicit a biologic response in the cytoskeleton and cellular membrane will ultimately lead to refined mechanotransduction relationships.

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“…But the mechanisms by which leukocytes sense fluid stresses are not well understood. The stress distribution on the surface of a leukocyte is complex and highly dependent on the fine geometric shape of the membrane 10. While the maximum shear stress at the top of an adherent cell increases as the cell retracts its pseudopod under fluid flow, pseudopod retraction occurs independently of the direction of shear 10.…”

Section: Introductionmentioning

confidence: 99%

“…The specific location of these receptors may be associated with the different shear responses that have been observed. Fluid shear stress acting on the leukocyte membrane is quite non-uniform 10. But little is known about the distribution of these surface receptors during fluid shear application.…”

Section: Introductionmentioning

confidence: 99%

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Internalization of Formyl Peptide Receptor in Leukocytes Subject to Fluid Stresses

Schmid‐Schönbein

2010

Cel. Mol. Bioeng.

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Human leukocytes retract pseudopods under normal physiologic levels of fluid shear stress even in the absence of any other mediator. To gain more detailed understanding of the mechanisms that regulate this cell behavior, we exposed leukocytes to a steady state laminar shear field in a flow chamber and computed the fluid stresses distribution on the surface of individual cells with and without pseudopod. The surface fluid stress distribution on such cell is quite inhomogeneous. We hypothesized that the local fluid stresses on the cell surface serve to regulate pseudopod retraction by way of membrane receptors, especially the formyl peptide receptor (FPR). Comparison of the receptor distribution and the stress distribution over the surface of the cells indicates that the membrane fluid stress alone is not directly correlated with the extent of regional pseudopod retraction, giving further support to the hypothesis that membrane receptors are involved in the mechanotransduction of leukocytes. We observed that after exposure to fluid shear the FPR was internalized to a small intracellular compartment. This internalization appears to be independent of the original location of the receptor on the surface of the cell and the FPR appears to be more derived from multiple locations on the cell, with both higher and lower fluid stresses. The evidence suggests that FPR involvement in the pseudopod-retraction process is not limited to cell surface regions with the highest fluid shear stress, but rather a more global occurrence over the majority of the cell membrane.

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Fluid Stresses on the Membrane of Migrating Leukocytes

Cited by 18 publications

References 20 publications

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Two-Dimensional Modeling of Nanomechanical Strains in Healthy and Diseased Single-Cells During Microfluidic Stress Applications

Internalization of Formyl Peptide Receptor in Leukocytes Subject to Fluid Stresses

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