Biomedical Engineering Reference
In-Depth Information
(e.g., via elevations in circulating levels of pro-inflammatory agonists or choles-
terol) leads to pathobiology of the circulation that will be discussed in a later
section as it relates to obesity.
4.3 Neutrophil Mechanosensitivity to Shear Stress
Up to this point, the accumulated evidence indicates that the sensitivity of neu-
trophils to fluid shear occurs (i) independent of cell adhesion and (ii) under a range
of magnitudes that do not elicit passive cell deformation [
107
]. These findings
implicate the cell membrane as the site at which mechanotransduction occurs.
Conceivably, the cell membrane may serve as a mechanotransducer through stress-
induced changes in its fluidity [
108
,
109
] or through lipid rafts [
110
,
111
].
However, this does not explain the cell type-specificity of shear stress mechano-
biology. A more plausible explanation is that the cell membrane is a mechano-
transduction compartment for cells. Moreover, the selectivity associated with
mechanotransduction depends on specific mechanoreceptor(s) or other mechano-
sensitive structures expressed on the cell surface. In line with this possibility, many
transmembrane proteins including various G protein-coupled receptors (GPCRs)
[
112
-
114
], tyrosine kinase receptors [
115
-
119
], ion channels [
120
], and integrins
[
121
,
122
] have been implicated as shear stress transducers for a variety of cells
(e.g., endothelial cells, osteoblasts) and microorganisms (e.g., dino-flagella) [
123
].
For neutrophils, two classes of membrane protein receptors have been impli-
cated as potential flow sensors: GPCRs and CD18 integrins. These receptors
reportedly undergo shear-induced structural shifts that manifest into downstream
functional responses (e.g., pseudopod retraction). Mechanosensitive signaling by
cytokine-related GPCRs/G proteins has been implicated in neutrophil mechano-
transduction since shear-induced pseudopod retraction is blocked by (i) monensin,
which raises cytosolic Na
+
and interferes with GPCR constitutive activity, and (ii)
pertussis toxin, a broad-spectrum G protein inhibitor [
92
]. Neutrophils express a
complement of GPCRs including those for fMLP, complement 5a, leukotriene B4,
IL-8, and PAF. Reports [
99
] documenting that shear-induced pseudopod retraction
is blocked by stimulation of cells with threshold concentrations of fMLP and PAF
further substantiate a potential relationship between GPCR activity and neutrophil
shear responses.
In fact, formyl peptide receptor (FPR), the GPCR for fMLP, has been impli-
cated as a shear sensor that drives downstream neutrophil responses to shear.
Notably, HL60-derived neutrophils subjected to shear stress have been shown to
display reduced Gia activity downstream of FPRs [
113
]. Moreover, when these
cells are transfected with siRNA to silence FPR expression, they exhibit an
attenuated pseudopod retraction response to shear despite retaining their capacity
to project pseudopods, likely governed by their intact expression of other cytokine-
related GPCRs [
113
]. But, the key evidence indicating that FPRs act as
mechanosensory regulators of pseudopod retraction is that overexpression of FPRs
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