Review Topical Sections

Phase relations of NASICON materials and compilation of the quaternary phase diagram Na2O-P2O5-SiO2-ZrO2

  • A short overview is given on existing phase relations in the four related ternary diagrams, setting the frame for a quaternary phase diagram. On the basis of published data the three-dimensional phase region of NASICON materials is constructed and phase relations to ternary and binary systems as well as to single oxides are presented. To date, the NASICON region can be described as a compressed tetrahedron within the tetrahedral phase diagram. However, the three-dimensional presentation clearly elucidates that few reported compositions exist outside this compressed tetrahedron indicating that the phase region of NASICON materials may be larger than the solid solutions known so far. The three-dimensional representation also better elucidates the regions connecting the edges of the NASICON tetrahedron with ternary and binary compounds as well as single oxides, i.e., ZrO2 and ZrSiO4, Na3PO4, sodium silicates and sodium zirconium silicates and gives a better understanding of phase formations during the processing of the ceramics. The implications of the formation of secondary phases and glass-ceramic composites are discussed in terms of technological applications.

    Citation: Frank Tietz. Phase relations of NASICON materials and compilation of the quaternary phase diagram Na2O-P2O5-SiO2-ZrO2[J]. AIMS Materials Science, 2017, 4(6): 1305-1318. doi: 10.3934/matersci.2017.6.1305

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  • A short overview is given on existing phase relations in the four related ternary diagrams, setting the frame for a quaternary phase diagram. On the basis of published data the three-dimensional phase region of NASICON materials is constructed and phase relations to ternary and binary systems as well as to single oxides are presented. To date, the NASICON region can be described as a compressed tetrahedron within the tetrahedral phase diagram. However, the three-dimensional presentation clearly elucidates that few reported compositions exist outside this compressed tetrahedron indicating that the phase region of NASICON materials may be larger than the solid solutions known so far. The three-dimensional representation also better elucidates the regions connecting the edges of the NASICON tetrahedron with ternary and binary compounds as well as single oxides, i.e., ZrO2 and ZrSiO4, Na3PO4, sodium silicates and sodium zirconium silicates and gives a better understanding of phase formations during the processing of the ceramics. The implications of the formation of secondary phases and glass-ceramic composites are discussed in terms of technological applications.


    1. Introduction

    Neutrophils are among the most numerous of all leukocytes (i.e., white blood cells) in the blood. Due to their high sensitivity to pathogenic stimuli and their vast destructive potential, tight regulation of neutrophil activity levels in the circulation is essential for maintaining blood in a physiological, non-inflamed state. Failure to do so promotes a continuous state of cell activation that drives downstream organ injury [1]. This may be in the form of dysregulated release of proteases and cytokines into the vasculature that ultimately damages host tissues (i.e., a form of autodigestion) [2]. Alternatively, sustained neutrophil activation in the blood may indirectly contribute to tissue damage by interfering with tissue perfusion through an impact on blood flow regulation. It may also affect the flow behavior of blood (i.e., rheology) in the microcirculation [3]. This rheological effect couples the changes in the biological (i.e., morphological and surface adhesive) properties of activated neutrophils to their viscous flow behavior in microvessels, which may have a detrimental impact on hemodynamic resistance in the peripheral circulation [4,5]. In these ways, neutrophils may promote tissue injury that feeds a chronic inflammatory state in the circulation, a condition that has been recognized as a common denominator for many lethal human pathologies (e.g. cardiovascular disease, cancer, diabetes, Alzheimer’s, etc.) [6,7].

    Although neutrophil inactivity/quiescence in the circulation is predicated on the absence of inflammatory agonists, cellular and molecular mechanisms exist to proactively ensure leukocytes, including neutrophils, remain deactivated under physiological conditions (i.e., in the absence of acute inflammatory stimuli) [8,9]. This includes a number of mechanisms involving release of anti-inflammatory mediators (e.g., interleukin-10, transforming growth factor-β, cyclooxygenase-2, nitric oxide) by endothelial cells [10,11,12]. These mediators act by either downregulating inflammatory cytokine secretion or preventing pro-inflammatory receptors from binding to their ligands. Notably, some of these involve endothelial mechanotransduction of hemodynamic shear stresses that control the release of molecules (e.g., nitric oxide) that prevent platelet and neutrophil activity (see reviews [13,14]).

    Over the past decade, we have contributed to a growing body of evidence [15,16] pointing to shear stress mechanotransduction by neutrophils as also being anti-inflammatory. During this time, we revealed new insights regarding how neutrophils respond to mechanical stresses in their local microscale environment and what factors influence this mechanoreception in health and disease. We also experienced a transition from using a reductionist viewpoint aimed at characterizing the shear stress responses of neutrophils to adopting a more global perspective to understand how the overall responsiveness of these cells to flow stimulation may play a role in vascular physiology and pathogenesis. What we have learned, thus far, is similar to that which has already been described; specifically, mechanotransduction is a complex process involving multiple pathways that converge upon a change (or changes) in cell activity. But the results of our efforts [17,18], and others [15,19,20], also suggest another concept; namely, there must exist some metric (e.g., mechanosensitivity) of the degree to which a cell’s activity is altered by mechanical stresses.

    In this review, we use the anti-inflammatory control of neutrophils by shear stress as the backdrop for discussing cell mechanosensitivity. Mechanosensitive events on the cell surface appear to be responsible for the ability of shear stress to restrict neutrophil activity by modulating intracellular signaling and/or extracellular events (e.g., adhesion receptor expression). Impairment of neutrophil mechanosensitivity is expected to result in tissue damage linked with reduced microvascular perfusion. This review will first describe neutrophil shear responses. We will then focus on some key mechanosensitive receptors/molecules on the cell membrane that participate in controlling neutrophil activity, followed by a description of the factors that may alter neutrophil mechanoregulation at the cell surface. Finally, we discuss how impaired neutrophil shear sensitivity may arise and promote pathobiology using two clinical scenarios: hypertension and hypercholesterolemia.

    2. Shear Stress Responses of Neutrophils

    In general, neutrophil mechanoregulation by fluid flow has largely been studied in context of their central role in acute inflammation. In this regard, neutrophils exhibit a number of responses to fluid flow-derived shear stresses of 0-18 dyn/cm2 [21,22,23] (Table1), which is the typical range reported for the post-capillary venules [21]. Depending on vessel size and leukocyte position in the bloodstream (whether on the vessel wall or suspended in the lumen), it is possible for neutrophils to experience this shear range in any blood vessel. Notably, neutrophils may be exposed to hemodynamic shear stresses that can reach up to 95 dynes/cm2 in some blood vessels [24]. However, since neutrophil recruitment during inflammation is generally limited to the post-capillary venules [25], the majority of studies, to date, have focused on neutrophil responses to shear stresses present within these microvessels. Notably, venular shear stresses are far below the >150 dynes/cm2 shear magnitudes that have been shown to induce mechanical trauma to neutrophils [26].

    Table 1. Effects of fluid flow on neutrophils.
    Neutrophil Shear Response Reference
    Pseudopod retraction [31]
    F-actin depolymerization [32]
    CD18 cleavage [18,30]
    FPR internalization [19,87]
    L-selectin shedding [33]
    Reduced phagocytosis [32]
    Apoptosis [34]
     | Show Table
    DownLoad: CSV

    The principal evidence of neutrophils requiring a flow environment to remain deactivated under non-inflamed or mildly stimulatory conditions is that fluid stasis activates them. Neutrophils deposited on glass substrates [27], even in the absence of inflammatory agonists [28], activate as evidenced by their projection of pseudopods and adherence to the underlying surface. Furthermore, there is a lower percentage of activated cells (based on their morphology and surface expression of select adhesion molecules) in a suspension of neutrophils after exposure to flow in a near-constant 5 ?10 dyn/cm2 shear stress field of a cone-plate viscometer, in comparison to those of cell populations maintained under no-flow, but otherwise similar, experimental conditions [29]. It has also been shown, by intravital microscopic examination of the microvasculature of murine cremaster and rat mesentery, that leukocytes in venules sediment to vascular walls, project pseudopods, and adhere to endothelium in response to upstream vessel occlusion when blood flow is stopped [15,30,31]. Upon reintroduction of blood flow, the neutrophils detach into the flow field in a mechanobiological, and not a physical shearing, fashion.

    One of the more overt manifestations of the neutrophil mechanosensitivity to shear stress is its morphological impact, particularly its effect on pseudopod activity. This particular response represents one of the more direct evidence that shear stress promotes neutrophil deactivation. Specifically, neutrophils migrating on glass substrates, in the absence of agonist stimulation, retract existing cytoskeletal F-actin enriched pseudopodia and adopt a rounded morphology within 1-2 min of the onset of exposure to a non-uniform flow field (τmax: 1-2 dyn/cm2) imposed by a micropipette (tip diameter of 4-8 μm) [31]. Moreover, shear stresses, in the range of 1 - 10 dyn/cm2 (typical of the circulation), elicit other effects consistent with neutrophil deactivation including depolymerization of the F-actin cytoskeleton and proteolytic cleavage of CD18 integrins (β2 family of integrins involved in cell-cell adhesion) [30,31]. These data fall in line with the likelihood that pseudopod retraction involves disassembly of the underlying F-actin network and rapid disengagement of cell adhesion molecules that support and anchor these cellular projections to the underlying surface. Additionally, exposure to physiologic shear stresses inhibits phagocytosis by neutrophils, which involves pseudopods [32]. Shear stress exposure has also been demonstrated to induce shedding of L-selectin, which may serve to minimize neutrophil rolling under flow [33]. Finally, another cell-deactivating effect of shear stress is its upregulation of caspase 3-related apoptosis [34], which is in line with the short lifespan (i.e., 18-24 hours) of neutrophils passively circulating in the blood.

    The cell-deactivating effects of shear stress mechanotransduction are consistent with it being an anti-inflammatory mediator of neutrophil activity. Evidence of this comes from in vitro and in vivo studies demonstrating that while low levels of cell agonists, such as fMLP (<1 μM) or platelet-activating factor (PAF, <10 μM) mildly stimulate neutrophils by promoting pseudopod formation, they do not compromise the ability of the cells to retract pseudopods in response to shear stress [27,30,31,35,36]. On the other hand, these same agonists above threshold levels (e.g., 1 μM fMLP, 10 μM PAF), which we believe demarcates an acute inflammatory scenario, abolish shear-induced pseudopod retraction [30]. Recently, we also showed a similar relationship between fMLP concentration and shear-related cleavage of CD18 integrins by HL60-derived neutrophil-like cells. Specifically, HL60 neutrophil-like cells exposed to shear in the presence of fMLP at concentrations >10 μM display an impaired ability to shed CD18 integrins [37]. Intuitively, this is reasonable since the blood biochemistry should be expected to override shear-induced deactivation of neutrophils when their heightened activity levels are required, such as during acute inflammation. Taken together, the accumulated evidence, to date, suggests that the shear stress regulation of neutrophils under physiological conditions is anti-inflammatory.

    A critical issue regards how hemodynamic shear stresses in the blood microenvironment are sensed by the neutrophils. Conceivably, initiation of mechanotransduction occurs at the interface between the cell interior and extracellular milieu (i.e., the cell membrane). Along this line, biological molecules on the cell surface appear to be responsible for the ability of shear stress to modulate cell activity. In effect, transmembrane proteins, while serving as receptors for autocrine and paracrine signaling molecules, also appear to “moonlight” as mechanosensors of shear stress. This is the subject of the next section.

    3. Shear Stress Sensitive Receptors Involved in Neutrophil Mechanoregulation

    An important aspect of neutrophil regulation by physiological shear stresses is that they affect the cell without inducing any passive cell deformation [38]. In other words, there must be cell surface components that initiate signaling pathways arising from mechanical stress perturbations in the extracellular milieu. Focal adhesion complexes (FACs) and intercellular junctional complexes have been widely reported to serve as sites of mechanotransduction for many cell types, including leukocytes [39,40,41,42]. The regulation of cell activity by substrate tensile stresses and matrix stiffness [43] has been largely attributed to these mechanosensory complexes. However, it is important to emphasize that neutrophils respond to shear stress with reduced pseudopod activity and CD18 surface expression, whether they are adhered to/migrating on a surface or freely suspended in solution [30,31,44].

    Additionally, neutrophils retract pseudopods independently of the spatial distribution of shear stresses imposed on their peripheral membrane by micropipette flow [31]. This was further supported in a later study that combined computational fluid mechanics with confocal microscopy of HL60-derived neutrophil-like cells retracting pseudopods in response to 2.2 dynes/cm2 shear stress exposure in a parallel plate flow chamber [45]. In this study, HL60 neutrophil-like cells retracted pseudopods independent of their orientation with respect to the long axis of the imposed flow field and the distribution of both normal and shear stress components that developed on the membrane. Along with these data, the cell surface has been implicated in shear stress mechanotransduction due to its strategic location between the intracellular and extracellular milieu as well as its cell-specific composition of receptors, signaling molecules, and second messengers [46,47,48].

    Conceivably, the cell membrane, itself, is a neutrophil mechanotransducer of shear stress considering the peripheral bilayer orchestrates the cyclical projection and retraction of pseudopods and uropods by influencing adhesion receptor function (such as CD18), ion transport (Ca2+, etc.), and cytoskeletal dynamics [49]. Interestingly, shear stress exposure has been shown to alter the fluidity of the cell membrane [48,50]. This may be one way by which neutrophils sense shear stress, because changes in membrane fluidity influence neutrophil phagocytosis [51,52] and migration by modulating chemokine receptor number and affinity [53,54]. Like other cells, neutrophils may also transduce shear stress through lipid rafts [55,56,57]. This is possible considering lipid rafts regulate neutrophil signal transduction (chemokine-induced calcium flux, cell polarization, migration, integrin expression, and actin dynamics, etc.) and functions (shape change, motility, etc.) [46,58,59], as well as CD18-mediated T-cell adhesion [60] and neutrophil adherence [61]. Thus, shear stress may modulate neutrophil activity via membrane mechanotransduction.

    However, the concept that the membrane serves as a mechanosensor lacks the cell-type specificity associated with shear stress mechanotransduction. This level of specificity likely depends on the peripheral membrane’s enriched content of cell-specific and highly selective receptors and signaling molecules, some of which may be mechanosensitive. Many cell membrane associated proteins (Table2) including various G protein-coupled receptors (GPCRs) [19,62,63,64,65,66], receptor tyrosine kinases (RTKs) [67,68,69,70,71,72,73], cell-cell adhesion molecules [39], ion channels [74,75,76], integrins [41,42,77,78,79], and signaling proteins (such as G-proteins [80,81]) have been implicated as shear stress sensors for various cells (e.g., endothelial cells, osteoblasts).

    Table 2. List of cell-specific mechanoreceptors.
    Mechanoreceptor Receptor Type Example Cell References
    Formyl peptide receptor (FPR) GPCR Leukocytes [19]
    CD18 integrins Integrin Leukocytes [18,30]
    L-selectin Selectin Leukocytes [33]
    Bradykinin B2 receptor GPCR Endothelial cells [63]
    Vascular endothelial growth factor receptor 2 RTK Endothelial cells [67]
    Tie2 receptor RTK Endothelial cells [70]
    PECAM-1/VE-cadherin Junctional complex Endothelial cells [39]
    Endothelin B receptor GPCR Smooth muscle cells [62]
    Epidermal growth factor receptor RTK Smooth muscle cells [68]
    Platelet-derived growth factor receptor-beta RTK Smooth muscle cells [72]
    Angiotensin II type 1 receptor GPCR Cardiac muscle cells [64,66]
    Type 1 parathyroid hormone receptor GPCR Osteoblasts [65]
    β1 integrins Integrin Various cells [77,78,79]
    Shaker-IR Voltage-gated K+ channel Transfected oocytes [74]
    TREK-1 Mechano-gated K+ channel Fibroblasts [75]
     | Show Table
    DownLoad: CSV

    For neutrophils, two cell surface receptors have been identified as putative mechanosensitive proteins that significantly contribute to the cell-deactivating effects of shear stress exposure; specifically, the formyl peptide receptor (FPR) and CD18 integrins.

    3.1. Formyl peptide receptor (FPR)

    FPR belongs to a group of cytokine-related GPCRs that modulate neutrophil activation, adhesion, and migration in response to chemotactic stimulation [82]. Makino et al. reported the initial evidence linking shear stress-induced pseudopod retraction and flow-mediated GPCR activity [15,19]. Specifically, they reported that both monensin, which interferes with GPCR conformational activity, and pertussis toxin, a broad-spectrum GPCR inhibitor, block shear-induced pseudopod retraction [19]. Furthermore, sheared HL60 neutrophil-like cells were shown to exhibit reduced G activity in line with flow-mediated downregulation of GPCR activity. Considering fMLP stimulation above threshold concentrations blocks fluid flow-induced pseudopod retraction [44], FPR, its high affinity GPCR, was viewed as a likely candidate mechanosensor for neutrophil responses to shear.

    Cell activation through fMLP stimulation, which elevates FPR activity, causes neutrophils to project pseudopods and upregulate their adhesion and migration on substrates [83]. It does so by modulating cytoskeletal remodeling, which includes an influence on the cyclical actin polymerization/depolymerization associated with pseudopod activity during cell migration [84]. F-actin dynamics are under the control of the RAS superfamily of guanine triphosphate (GTP)-binding proteins, including the small GTP-phosphatases (GTPases): Rac1, Rac2, cdc42, and the Rho GTPases [85,86]. Fluid shear stress exposure reduces Rac1 and Rac2 activity consistent with it causing retraction of existing, or preventing the formation of new, actin-enriched pseudopods by neutrophils [15]. These data further suggested a role for GPCRs as mechanotransducers of shear stress for neutrophils.

    Notably, FPR appears to be critical for neutrophils to project pseudopods considering that undifferentiated HL60 cells, which do not express FPR, lack the ability to form pseudopods [19]. On the other hand, transfecting FPR expression plasmids into HL60s imparts on these cells the ability to form pseudopods that retract under the influence of fluid shear stress [19]. The key evidence implicating FPR as a shear sensor, however, was that transfecting differentiated HL-60 neutrophil-like cells with siRNA to silence FPR expression inhibited their shear-induced pseudopod retraction response, despite the fact that these cells retained the ability to project pseudopods due to the presence of other cytokine-related GPCRs [19].

    While precisely how shear stress reduces FPR activity on the cell surface remains unclear, it does not involve the activity of matrix metalloproteinases (MMPs) [20], which are capable of cleaving FPR [87]. Instead, it possibly involves shear-induced internalization and relocalization of FPR from the cell surface to a perinuclear compartment [88]. Fluid shear-induced internalization of FPRs may therefore serve to minimize their constitutive activity on the cell surface, which in turn minimizes pseudopod activity. But, apparently, some FPRs must be present on the cell surface, since proteolytic FPR cleavage impairs the ability of shear stress to induce neutrophil pseudopod retraction [87].

    3.2. CD18 integrins

    CD18 integrins play an important role in neutrophil adhesion and migration. They form the β2-subunit of four integrin heterodimeric complexes: lymphocyte function antigen-1 (LFA-1 or CD11a/CD18), macrophage-1 antigen (Mac-1 or CD11b/CD18), integrin αXβ2 (CD11c/CD18), and integrin αDβ2 (CD11d/CD18) [89]. Among these, CD11a/CD18 and CD11b/CD18 are critical for neutrophil-substrate interactions [18,44,90]. While CD11a/CD18 is involved in loose capture interactions that promote neutrophil arrest, CD11b/CD18 enables the neutrophil to become firmly adhered to substrates while withstanding the shearing forces applied by the surrounding blood flow. Once adhered, neutrophils become capable of migration and extravasation along chemotactic gradients toward sites of damaged tissue [1]. As a result, these two integrins play key roles in neutrophil recruitment during inflammation [91,92].

    Similar to FPR, shear stress exposure downregulates expression of CD18 integrins on the neutrophil surface. This downregulation differs from FPR, however, since it relies on the enzymatic activity of proteases that cleave CD18 integrins, particularly CD11b/CD18 for neutrophils [18]. Reportedly, the CD11b and CD18 integrin subunits are cleaved by the cysteine protease cathepsin B (catB) [37,44]. Additionally, cleavage of these integrins occurs in the ectodomain presented on the outer surface of the cells [17], suggesting that catB is released from lysosomal stores into the extracellular milieu. The exact mechanisms that cause catB to be released into the extracellular milieu in response to shear stress exposure, however, remain to be elucidated.

    Interestingly, CD18 integrins may act as mechanosensors. In addition to their cleavage by catB, evidence suggests that fluid shear stress exposure promotes conformational shifts in the CD18 extracellular domain [17]. These shear-induced conformational shifts appear to facilitate catB access to its cleavage site. But, it is also possible that they promote outside-in signaling and alter cell activity. Up to this point, however, the existing evidence only suggests that shear-induced CD18 cleavage removes the extracellular ligand-binding domain, thereby preventing neutrophils from adhering to substrates. As a result, this shear-induced CD11b/CD18 cleavage may not be viewed as following the classical paradigm of mechanoreception/mechanotransduction. However, a case can be made that this shear response may represent another way by which neutrophils sense their flow environment and alter their function. In this case, CD18 integrins sense and transduce an applied shear stress stimulus into a biological event by changing their conformational activity (i.e., mechanotransduction). In turn, this mechanoreceptive event, rather than inducing cellular signaling, enables proteases to cleave integrins off the membrane surface, which manifests as a change in cell adhesion involved in a number of important neutrophil functions (e.g., phagocytosis, migration, etc.).

    In summary, both FPR and CD18 integrins play crucial roles in the adhesion, migration, and defensive capabilities of human neutrophils. Furthermore, shear exposure minimizes the activity of these two surface receptors to prevent neutrophil activation under physiologic (i.e., non-inflamed) conditions. Although shear stress results in downregulation of both FPR and CD18 activity, the exact mechanotransduction mechanism differs in both cases.

    4. Neutrophil Mechanosensitivity

    In general, fluid shear stress mechanotransduction by vascular cells under physiological (non-diseased, non-pathogenic) conditions serves to maintain their quiescence (i.e., baseline activity) [93]. This view has evolved from a plethora of investigations regarding the various mechanosignaling pathways and mechanosensors that were conducted in a reductionist fashion where cells were analyzed under uniform and controlled stress regimes [94,95]. However, vascular cells, including the neutrophils, experience large variations in fluid stress levels from moment to moment, and they function under a diversity of mechanical stress distributions and magnitudes [96,97]. Thus, atypical stress distributions that arise due to some physiological or pathological event are unlikely to be the sole cause of chronic cell dysfunction. What may change and result in their abnormal cell activity, however, is their responsiveness to applied stresses (i.e., their mechanosensitivity).

    Just as sustained chemical perturbations in the blood or changes in cell surface biochemistry may alter vascular cell activity and lead to potential pathobiology or altered tissue function, changes in cell mechanosensitivity may also impact vascular health. Along this line, the peripheral membrane appears to be in a position to serve as the mechanosensory compartment that enables cells to sense their mechanoenvironment and adjust their activity [50,98,99]. Considering that fluid flow mechanotransduction is predicated on the ability of shear stress to induce changes in the conformational activity of proteins leading to downstream signaling [100,101], it is conceivable that the mechanosensitivity of a cell depends on a number of aspects of its mechanotransducing machinery. Principally, it depends on the number of mechanosensors on the cell surface. It also may depend on the ability of these mechanosensors to deform under applied shear stresses, which likely are functions of the mechanical properties of the mechanosensor or the mechanical properties of the support medium in which the mechanosensors reside.

    For neutrophils, the numbers of FPR and CD18 integrins on the cell surface influence their shear stress sensitivity. Notably, cleavage of FPR from the surfaces of neutrophils treated with proteases results in their impaired pseudopod retraction response to shear [87]. In the case of CD18 integrins, although they are cleaved in response to shear, a baseline level of their presence on the cell surface may be required to allow these cells to retract pseudopods in response to fluid shear stress. In support of this, pretreatment of neutrophils with CD18 antibodies blocks their ability to retract pseudopods under shear stress [102].

    Additionally, neutrophil mechanosensitivity likely depends on the ability of mechanical stresses to alter the conformation of putative mechanosensors. Currently, there is evidence that shear stress promotes changes in the activity of many protein receptors for a number of cells, including the neutrophils. But there is little direct evidence that changes in the “deformability” of these mechanosensors will alter cell mechanosensitivity. Conceivably, this may occur as a result of genetic mutations in the amino acid sequence. Studies focusing on the inside-out related conformational shifts in integrins, which are required to promote counter-receptor binding, have demonstrated the effects of such genetic mutations. For example, point mutations to the I-domain of CD11b integrins stabilize the “open” (active) conformation of these receptors and promote ligand binding [103]. Specific point mutations to the amino acid sequence of glycoprotein IIb/IIIa also enhance ligand binding [104]. In this regard, mutations in FPR and/or CD18 integrins may alter the ability of shear stress to induce conformational activities in these receptors with an impact on neutrophil mechanosensitivity to flow. But, to date, the existence of naturally occurring genetic changes in protein structure that alter cellular responses to mechanical stimuli remains to be seen. Moreover, it is unknown whether post-translational modifications may be another source of altered mechanosensitivity.

    Finally, it is possible that the physical properties of the support medium for the mechanosensors (i.e., the cell membrane) influence mechanosensitivity by affecting the ability of putative mechanoreceptors to “deform” under flow stimulation. The neutrophil membrane is the support medium for, and governs the conformational activity of, FPR and CD18 integrins. Conceivably, this includes influencing the ability of shear stress to induce conformational changes. Such a possibility is consistent with the influence of the cell membrane properties, particularly membrane fluidity, on chemokine receptor surface concentrations and affinities for ligands in the regulation of neutrophil adhesion and chemotaxis [51,52,53,54]. In the most general sense, changes in membrane fluidity likely alter receptor dynamics by influencing their intermolecular interactions (with other signaling molecules) or by modulating their structural activity due to ligand binding that controls downstream cell signaling [105]. For example, altered lipid bilayer fluidity changes the number, affinity, lateral mobility, and conformational activity of membrane receptors (e.g., GPCRs, concanavalin A receptor) [63,106]. In this fashion, membrane fluidity regulates neutrophil sensitivity to cytokine ligands that stimulate cell functions (e.g., migration, phagocytosis, growth, and differentiation) [53,54].

    It turns out that membrane fluidity may also influence neutrophil mechanosensitivity. Along this line, we addressed, in a recent paper [36], the question of how changes in membrane cholesterol content associated with disease states (i.e., hypercholesterolemia) might negatively impact the anti-inflammatory control of neutrophils by fluid shear stress. Among its many biological functions, cholesterol, a structural component of the lipid bilayer, regulates the cell membrane fluidity [107]. In the context of cellular physiology, while membrane cholesterol enrichment decreases lipid bilayer fluidity, membrane cholesterol depletion increases it [108,109]. Furthermore, cholesterol-related modification of the cell membrane has been shown to alter chemokine-related signaling in neutrophils with an effect on their membrane ruffling, cell polarization, and F-actin polymerization during activation with fMLP [110,111].

    Cholesterol also appears to govern cell responses to shear stresses. For example, shear-dependent activation of extracellular signal-related kinase (ERK) in endothelial cells is inhibited by depleting membrane cholesterol content [112]. Similarly, membrane cholesterol depletion alters osteoblast mechanosignaling in response to shear stress exposure [55]. These results suggested that membrane cholesterol levels influence mechanotransduction processes, but it was unclear whether this influence is due to the effects of cholesterol on membrane fluidity or compartmentalization into lipid raft-enriched regions. Recently, we reported evidence that neutrophil mechanosensitivity depends on cholesterol-related membrane fluidity [36]. We also revealed the existence of an optimal membrane cholesterol/fluidity range that is permissive for the cell-deactivating effects of shear stress; above or below this range, the fluid shear stress responses of neutrophils are blocked [36]. Thus, the cholesterol-related fluidity of the cell membrane may be a modulator of neutrophil mechanosensitivity.

    Overall, neutrophil mechanosensitivity appears to be a function not only of the mechanosensors that permit the cell to sense their local mechanoenvironment, but also of the mechanical properties of the cells themselves. In this regard, it is clear that cell mechanosensitivity may be an important parameter that determines the difference between physiology and pathobiology.

    5. Neutrophil Mechanosensitivity Perspective to Cardiovascular Pathophysiology

    Notably, hypertension and hypercholesterolemia are associated with chronically inflamed blood typified by sustained elevations in the numbers of activated neutrophils in the circulation [113,114]. These disease states may serve to promote microvascular inflammation and impaired tissue blood flow regulation long before the onset of lethal vascular diseases (Figure 1). This inflammation is believed to drive microcirculatory dysfunction that interferes with tissue blood flow regulation and ultimately leads to detrimental effects on the macrocirculation [1,3]. What is missing from this explanation, however, is the mitigating event that links hypertension or hypercholesterolemia with the onset of dysregulated neutrophil activity/adhesion in the microcirculation.

    Figure 1. Proposed impact of an impaired neutrophil mechanosensitivity to shear stress on the microcirculation. Blue arrows represent the regulation of neutrophil activity under physiological (i.e., non-diseased, non-inflamed) conditions. In absence of inflammatory stimuli, neutrophils remain quiescent due, in part, to the deactivating effects of shear stress mechanoregulation. Exposure to pro-inflammatory stimuli activates neutrophils and promotes inflammation. Neutrophils remain activated until agonist levels subside during resolution of inflammation, at which point neutrophils become quiescent. The red arrows represent the effects of pathological conditions, such as hypertension or hypercholesterolemia. By impairing the neutrophil response to shear stress, these pathological conditions likely promote sustained neutrophil activation in the blood. This, in conjunction with elevated plasma levels of cytokines/agonists, eventually results in chronic inflammation. The accumulation of activated neutrophils in the microvasculature during chronic inflammation is then thought to drive dysregulated microvascular flow and downstream cardiovascular diseases.

    To date, we have accumulated evidence implicating neutrophil mechanoregulation as an important control mechanism [35]. More specifically, shear stress mechanosensitivity appears to ensure that neutrophils remain in an inactivated, quiescent state to minimize inflammatory activity in the blood in the absence of some mitigating pathogenic event. In the event that these mechanotransduction processes become dysregulated, it is conceivable that the ensuing spontaneous activation of neutrophils would promote microvascular dysfunction and, eventually, the progression of cardiovascular disease.

    Recent studies suggest that dysregulated neutrophil activity may contribute to the progression of various lethal cardiovascular disease states [2,36,115,116]. There is evidence that this neutrophil dysregulation may arise, at least in some cases, due to changes in the ability of fluid shear stress to deactivate neutrophils [116]. Notably, such changes may be best described by modifications to the surface biochemistry or properties consistent with a change in their mechanosensitivity. For example, evidence has been reported that indicates the impaired shear responses of neutrophils from spontaneously hypertensive rats may be due to increased proteolytic activity in the blood that cleaves FPR receptors off the cell surface [87]. Due to FPR cleavage, pseudopods would remain extended on neutrophils, a feature linked to elevated hemodynamic resistance [115]. Neutrophils from hypercholesterolemic mice also exhibit an impaired pseudopod retraction response to fluid shear stress, which had been attributed to a potential effect of cholesterol on cell membrane fluidity [36]. These studies suggest that neutrophil mechanosensitivity is a determinant of blood health, since impaired perfusion due to pseudopod extensions may lead to tissue damage and progression of cardiovascular diseases.

    6. Final Remarks

    Recognition of shear stress mechanosensitivity as a metric of the health status of neutrophil mechanoregulation opens the door to new possibilities in terms of understanding disease pathogenesis and progression. At the same time, it provides the basis for developing novel therapeutic and diagnostic approaches to address the origins or causes of cardiovascular disease and possibly even other pathological conditions. In the end, a research strategy that adopts a global cell mechanosensitivity perspective in conjunction with a focused reductionist approach may lead to a better understanding of the contribution of mechanobiology to physiology and pathobiology.

    Conflict of Interest

    All authors declare no conflicts of interest in this review.

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