Biomedical Engineering Reference
In-Depth Information
Fig. 4 Inflammatory agonists dose-dependently attenuate the CD18 shear response. Under
physiologic (i.e., non-inflamed, [fMLP] = 0) conditions, CD18 integrins are cleaved off the
surfaces of HL60 neutrophilic cells during shear exposure. However, this cleavage response is
attenuated for [fMLP] C1 lM in a similar fashion to that reported [
99
] for shear-induced
pseudopod retraction. For our analyses, we quantified the mean fluorescence intensities (MFI) of
CD18 antibody binding by HL60 neutrophilic cells after exposure to 5 dynes/cm
2
shear stress
normalized to their respective unsheared controls and expressed as ''CD18 expression index''.
Bars are mean CD18 expression index ± standard error of the mean (SEM); n = 3. *p\0.05
compared to hypothetical value of 100 % remaining integrin (dashed line), ^p\0.05 compared to
cells exposed to shear in presence of 0, 0.01, or 1 lM fMLP [
102
]
in cell migration by promoting the retraction of uropods, specialized pseudopods
formed at the trailing edge of a migrating cell. But rather than stimulating RhoA
activity or expression levels to promote retraction of cell processes, shear stress
appears to either inhibit (e.g., possibly through release of an inhibitor) or interfere
with the ability of neutrophils to form and sustain pseudopod projections [
92
].
It does so by reducing cytosolic Rac1 and Rac2 activity, thus preventing actin
polymerization [
92
].
Shear stress exposure also reduces the surface expression of CD18 integrins that
play a major role in neutrophil recruitment during acute inflammation [
104
-
106
].
Specifically, exposure of neutrophils to shear stress elicits proteolysis of CD11b/
CD18 (but not CD11a/CD18) integrins [
106
], likely due to the rapid release of
cathepsin B (catB) proteases [
104
,
105
]. One effect of this shear response is the
reduction in neutrophil binding to platelets after 10 minutes of flow exposure [
106
].
Notably, shear stress also leads to cleavage of CD18 integrins bound to ligands
on the substrates of migrating neutrophils [
104
]. In this way, catB may mediate
shear-induced pseudopod retraction. Taken together, flow-mediated catB release
appears to prevent formation of new attachments by adhered or suspended cells
and/or promote pseudopod retraction at sites of CD18 attachments by migrating
neutrophils.
In summary, shear stress mechanotransduction (i) induces multiple physical
manifestations of neutrophil deactivation, (ii) involves cell signaling in line with
reduced cell activity, and (iii) is a robust feature of the neutrophil phenotype, all of
which are in line with its anti-inflammatory role. In this way, we predict that the
neutrophil mechanosensitivity to shear is linked to the vascular physiology.
Moreover,
dysfunction
or
blockade
of
neutrophil
shear
mechanosensitivity
Search WWH ::
Custom Search