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Fig. 5 Possible ways by which membrane cholesterol enrichment impairs neutrophil mecha-
notransduction of shear stress. Elevations in extracellular cholesterol lead to membrane
cholesterol enrichment that may alter cell mechanosensitivity either by influencing shear-induced
structural changes of cell surface sensors (e.g., GPCRs, CD18 integrins) or by interfering with
shear-induced release of lysosomal proteases (e.g., catB)
Interestingly, cholesterol, an essential component of the cell membrane, is a
regulator of membrane fluidity [
133
-
135
]. Increasing the cholesterol content of the
cell membrane reduces its fluidity, while reducing membrane cholesterol levels
has the opposite effect [
133
,
134
]. In general, the cholesterol-related fluidity of the
cell surface has been reported to influence neutrophil chemokine-related signaling
such as fMLP-induced membrane ruffling, polarization, and F-actin polymeriza-
tion [
136
,
137
].
Recently, we showed neutrophil mechanosensitivity to be a function of cho-
lesterol-related membrane fluidity [
9
]. Specifically, benzyl alcohol (BnOH), a lipid
fluidizer, selectively offset the blocking effects of membrane cholesterol enrich-
ment on shear-induced pseudopod retraction by neutrophils mildly stimulated with
fMLP [
9
]. We also demonstrated the existence of an optimal membrane choles-
terol/fluidity level permissive for shear-induced deactivation of these cells [
9
].
Collectively, these results implicated the cholesterol-related fluidity of the cell
membrane as a modulator of neutrophil mechanosensitivity to fluid flow. For
example in conjunction with the dependence of GPCR activity or redistribution/
internalization on membrane cholesterol content, it is conceivable that the influ-
ence of shear stress on neutrophil pseudopod activity is impacted by perturbations
in extracellular membrane cholesterol abundance due to its influence on mecha-
nosensor dynamics.
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