Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity - The Mechanobiology of Obesity and Related Diseases - page 211

The results from our prior study [ 9 ] also hint at the likelihood that shear-induced
CD18 cleavage is affected by the membrane properties, since these integrins
undergo flow-induced structural shifts [ 105 ]. Interestingly, shear-related CD18
cleavage also requires the release of proteases that must cross the membrane [ 104 ,
105 ] and that may depend on the lipid bilayer properties. Thus, the cholesterol-
related properties (i.e., fluidity) of the membrane may govern neutrophil shear
sensitivity by its effects on catB transport across the cell surface (Fig. 5 ).
4.4 Influence of the Neutrophil Shear Responses
on the Microcirculation
The importance of the fluid flow mechanoregulation of neutrophil activity to
microvascular physiology is apparent when considering how impaired neutrophil
shear responses may impact the microcirculation. As a result of such attenuation,
neutrophils have been shown to exhibit a greater tendency to become entrapped in
capillaries and adhere to venules in rats [ 99 , 100 ]. In this way a deficit in the
neutrophil shear responsiveness raises peripheral resistance with downstream
impacts on tissue perfusion that may lead to organ injury [ 138 ].
Principally, the functional responses of neutrophils to shear stress impact
microvascular hemodynamics via an influence on their flow behavior in the
microcirculation. In effect, shear-induced cell deactivation appears to serve as a
control mechanism that ensures neutrophils navigate the microcirculation in a
mechanically-passive, suspended, and non-adhesive state. This would enable them
to freely-deform and pass through the smaller vessels of the microcirculation [ 11 ].
In a seminal study, Moazzam et al. [ 100 ] showed by intravital microscopy that
neutrophils migrating on venules, due to the actions of upstream blood flow
occlusion-induced blood stasis in the rat microcirculation, retracted pseudopods,
detached from the vessels, and flowed out of the visual field during flow reper-
fusion in the absence, but not presence, of inflammatory agonists. This study
indicated that the neutrophil shear sensitivity also serves to minimize microvas-
cular adhesion in the non-inflamed setting.
Notably, membrane disengagement during pseudopod retraction or cell detach-
ment by migrating neutrophils in response to shear stress points to two fundamental
requirements that must be fulfilled by the cell mechanosignaling apparatus: (i)
depolymerization of cytoskeletal F-actin that makes up the mechanical support
structure and signaling framework for cell motility, and (ii) rapid detachment of
adhesion receptors that anchor the pseudopod or cell body to the underlying matrix.
During acute inflammation, neutrophils make one of their first adhesive contacts
with the venules via CD11b/CD18 binding to endothelial cells or indirectly via
platelet binding. A major impact of neutrophil adhesion in the microcirculation is to
reduce microvascular cross-sectional area which profoundly alters flow resistance
(Fig. 3 , Geometric effect). Thus, for the non-inflamed scenario, shear-related