Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity

Xiaoyan Zhang, Jonathan Hurng, Debra L. Rateri, Alan Daugherty, Geert W. Schmid-Schönbein, Hainsworth Y. Shin

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Continuous exposure of polymorphonuclear leukocytes (PMNLs) to circulatory hemodynamics points to fluid flow as a biophysical regulator of their activity. Specifically, fluid flow-derived shear stresses deactivate leukocytes via actions on the conformational activities of proteins on the cell surface. Because membrane properties affect activities of membranebound proteins, we hypothesized that changes in the physical properties of cell membranes influence PMNL sensitivity to fluid shear stress. For this purpose, we modified PMNL membranes and showed that the cellular mechanosensitivity to shear was impaired whether we increased, reduced, or disrupted the organization of cholesterol within the lipid bilayer. Notably, PMNLs with enriched membrane cholesterol exhibited attenuated pseudopod retraction responses to shear that were recovered by select concentrations of benzyl alcohol (a membrane fluidizer). In fact, PMNL responses to shear positively correlated (R 2 = 0.96; P < 0.0001) with cholesterol-related membrane fluidity. Moreover, in low-density lipoprotein receptor-deficient (LDLr -/-) mice fed a high-fat diet (a hypercholesterolemia model), PMNL shear-responses correlated (R 2 = 0.5; P < 0.01) with blood concentrations of unesterified (i.e., free) cholesterol. In this regard, the shear-responses of PMNLs gradually diminished and eventually reversed as free cholesterol levels in blood increased during 8 wk of the high-fat diet. Collectively, our results provided evidence that cholesterol is an important component of the PMNL mechanotransducing capacity and elevated membrane cholesterol impairs PMNL shearresponses at least partially through its impact on membrane fluidity. This cholesterol-linked perturbation may contribute to dysregulated PMNL activity (e.g., chronic inflammation) related to hypercholesterolemia and causal for cardiovascular pathologies (e.g., atherosclerosis).

Original languageEnglish
Pages (from-to)C451-C460
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Cell deactivation
  • Flow
  • Hypercholesterolemia
  • Mechanotransduction
  • Pseudopod retraction

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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