Biomedical Engineering Reference
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in undifferentiated HL60 promyelocytes not only confers expression of this
receptor, but also imparts on these cells the ability to form pseudopods that retract
under the influence of fluid shear stress [ 113 ]. Together, this evidence substanti-
ated the putative role of membrane-bound GPCRs, particularly FPRs with high
constitutive activity, in the neutrophil pseudopod retraction response to shear
stress.
While the exact involvement of FPRs remains unknown, it appears that fluid
shear stress promotes internalization and relocalization of FPRs from the cell
surface to a perinuclear compartment [ 124 , 125 ]. It is believed that internalization
of FPRs under fluid shear counteracts their constitutive activity on the cell surface,
which reduces pseudopod activity. However, some FPRs must be present on the
cell surface, since cleavage of FPRs impairs the ability of shear stress to induce
neutrophil pseudopod retraction [ 126 ].
In addition to FPRs, neutrophil mechanotransduction also depends on CD18
integrins. Reportedly, CD18 integrin activity is required for shear-induced pseu-
dopod retraction by neutrophils on substrates [ 127 ]. Interestingly, CD18 has been
shown to undergo rapid shear-induced conformational shifts in its extracellular
domain, within 1 minute of flow onset, upstream of its cleavage from neutrophils
[ 105 ]. Conformational activity of CD18 integrins promotes outside-in signaling
[ 105 ]. Thus, CD18 integrin shear-induced structural shifts may promote intracel-
lular signaling that influences neutrophil activity, in addition to exposing putative
cleavage sites on the receptor ectodomain for access by cysteine proteases such as
catB released from cytosolic granules [ 104 ].
Therefore, the collective evidence points to transmembrane receptors serving
as the link between extracellular flow conditions and cellular activities upstream of
neutrophil functional responses to shear. Along this line, it is likely that the
numerous mechanoreceptors, such as FPRs and CD18 integrins, confer on the
neutrophils a sensitivity to shear flow [ 105 , 126 ].
It, however, is also conceivable that the neutrophil mechanosensitivity depends
on the mechanical properties of the cell membrane, across which these mechano-
receptors span (Fig. 5 ). Notably, the cell membrane serves as the substrate for, and
governs the structural activity of, FPRs and CD18 integrins. As such, its physical
properties (e.g., fluidity) likely govern mechanosensitivity by impacting the shear-
related structural activity of these putative mechanosensors (Fig. 5 ). Such a concept
agrees with the role of the cell membrane in orchestrating pseudopod activity and
cell adhesion [ 128 ], both of which are affected by shear exposure.
Generally, changes in membrane fluidity alter the dynamics of membrane
protein activity, either by affecting their intermolecular interactions or by modu-
lating their structural activity, thereby affecting downstream cell signaling and
functions [ 129 ]. Changes in lipid bilayer fluidity have been shown to influence the
number, affinity, lateral mobility, and conformational activity of membrane
receptors (e.g., GPCRs and concanavalin A receptor) during ligand-induced acti-
vation [ 112 , 130 ]. In this fashion, membrane fluidity appears to regulate neutrophil
sensitivity
to
cytokine
ligands
that
stimulate
cell
functions
(e.g.,
migration,
phagocytosis, growth, and differentiation) [ 131 , 132 ].
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