Originally published online as doi:10.1189/jlb.1106710 on March 14, 2007
Published online before print March 14, 2007
(Journal of Leukocyte Biology. 2007;81:1160-1164.)
© 2007
by Society for Leukocyte Biology
Leukocyte membrane "expansion": a central mechanism for leukocyte extravasation
Sharon Dewitt and
Maurice Hallett1
Neutrophil Signalling Group, School of Medicine, Cardiff University, Cardiff, United Kingdom
1 Correspondence: Neutrophil Signalling Group, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. E-mail: hallettmb{at}cf.ac.uk
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ABSTRACT
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The infiltration of inflamed tissues by leukocytes is a key event in the development and progression of inflammation. Although individual cytokines, which coordinate extravasation, have become the targets for therapy, a mechanism that is common to white cell extravasation, regardless of the specific molecular mechanism involved, would represent a more attractive therapeutic target. Such a target may be represented by the events underlying the spreading of leukocytes on the endothelium, which is a necessary prelude to extravasation. This leukocyte "spreading" involves an apparent increase in the cell surface area. The aim of this review is to examine whether the mechanism underlying the apparent expansion of plasma membrane surface area during leukocyte extravasation could be an "Achilles’ heel," which is amenable to therapeutic intervention. In this short review, we evaluate the models proposed for the mechanism of membrane "expansion" and discuss recent data, which point to a mechanism of membrane "unwrinkling." The molecular pathway for the unwrinkling of the leukocyte plasma membrane may involve Ca2+ activation of µ-calpain and cleavage of cytoskeletal linkage molecules such as talin and ezrin. This route could be common to all extravasation signals and thus, represents a potential target for anti-inflammatory therapy.
Key Words: adhesion • neutrophil • calcium
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INTRODUCTION
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The infiltration of inflamed tissues by leukocytes, especially lymphocytes and neutrophils, is a key event in the development and progression of inflammation. This is signaled by an array of cytokines, which have become the targets for therapy individually, such as in the case of anti-TNF therapy. However, the identification of a mechanism common to white cell extravasation, regardless of the specific molecular mechanism involved, may represent a susceptible target, which could be attacked beneficially. Neutrophils, macrophage/monocytes, and lymphocytes adhere to endothelium and undergo a change from a spherical to a flattened morphological. This is required for firm adhesion and is the necessary prelude for transmigration through the endothelium, whether by migration between the endothelial cells or "through" an endothelial cell [1
]. The morphology change requires a large expansion of the surface area of the leukocytes. The molecular pathway involved in this "unwrinkling," which would be common to all extravasation signals, would thus be an Achilles’ heel and represent potential targets for anti-inflammatory therapy. In this short review, we evaluate the models proposed for the mechanism of membrane expansion and discuss recent data, which point to a mechanism of membrane unwrinkling.
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LEUKOCYTE PLASMA MEMBRANE EXPANSION DURING EXTRAVASATION
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When neutrophils flatten out onto endothelial cells, the transformation from the spherical to the flattened (spread) morphology is dramatic. As the spherical geometry is the minimum surface area required to enclose a certain volume, it is obvious that the volume of the cell must decrease, or its surface area must increase during this transformation. In fact, it is the surface area of the cell that increases during flattening onto the endothelium. For cells like neutrophils, where the intracellular organelles such as the nucleus and granules occupy a large percentage of its volume, there is little possibility of a volume change in any case. The increase in surface area, however, is surprisingly large, with an increase by more than 100% (see Fig. 1a
). This doubling of surface area must be explained. Could the lipid bilayer of the plasma membrane "stretch" this far, or are additional sources of membrane (membrane reservoirs) required? If additional membrane is required, the mechanism by which it is called on must also be explained.
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Figure 1. Cartoons showing the morphology change during flattening of a sphere of fixed volume against a flat surface. (a) The surface area was calculated as  (2x2+h2), where x is the radius of the contact surface, and h is the height of the cell and is shown as a percentage of the initial area. (b) SEMs of the "spherical," nonadhered cell (showing multiple surface wrinkles) and the flattened morphology with loss of wrinkling. b, Reproduced with permission [2
].
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METHODS OF MEMBRANE EXPANSION
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The first possibility is that the plasma membrane is able to stretch this far, as if it were elastic. However, the structure of the plasma membrane makes this impossible. The plasma membrane is essentially a phospholipid bilayer with inserted proteins held together as a sheet by laterally cohesive forces between the lipid molecules. The cohesion of the sheet, therefore, depends on the hydrophobic interactions of the fatty acid chains excluding water. Any "stretching" effect on the bilayer, which laterally separates the lipid molecules and allows water molecules between the lipid, will cause rupture of the bilayer. The proteins in a biological membrane may permit a little additional stretch, but it has been shown experimentally (and theoretically calculated) that biological membrane and simple phospholipid bilayers can expand by no more than 
4% before rupturing [3
]. There is thus far too little stretch in the plasma membrane to account for the expansion of surface area required for cell flattening during adhesion to the endothelium. This lack of stretchiness of lipid bilayers means that there must be a reservoir of membrane, which is made available for the plasma membrane to expand during adhesion.
A source of membrane could be provided by intracellular membranes, which enclose secretory granules within the cell. Exocytosis (or degranulation) of these granules would insert additional membrane into the plasma membrane. There are two problems with this source of membrane. The first problem is that fusion of the membrane of the granule with the plasma membrane would also release the contents of the vesicle into the extracellular space. In neutrophils, for example, the granules contain hydrolases and other degradative enzymes, which could be disastrous for the underlying endothelium. However, release of granular content [4
] and the localized release of myeloperoxidase, a major intragranular protein in neutrophils, have been reported to occur during extravasation [5
]. This would presumably add extra membrane to the neutrophil surface. However, this brings the second major problem for proposing intracellular vesicles as the membrane reservoir, namely, that it would be insufficient to account for the required membrane expansion. A single granule with a diameter of 0.2 µm (1/50th the diameter of a neutrophilic phagocyte) would contribute only 0.04% additional membrane area. Doubling the surface area would require 2500 vesicle fusion events/cell to occur, which would account for all the granules within the granulocyte. The increase in membrane capacitance of neutrophils during exocytosis is directly proportional to its additional surface area and so can be used as experimental support for this simple calculation [6
]. Such a massive release of granular material does not occur during extravasation. In fact, it is difficult to release more than one-third of the vesicle content experimentally, even when "artificial" strategies are used such as adding cytochalasin B. The release of all the granular content in the vicinity of the endothelium could also be catastrophic. In less granular cells, such as lymphocytes, even fusion of all granular membrane would be insufficient to provide the additional membrane.
The third proposal is that the plasma membrane wrinkles provide the membrane reservoir for expansion during extravasation. The extent of this reservoir has been demonstrated by applying suction to the neutrophil surface through a micropipette. Under this physically applied force, the neutrophil plasma membrane can undergo large expansions [7
8
9
].
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WRINKLES IN THE PLASMA MEMBRANE AS THE EXPANSION RESERVOIR
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A scanning electron micrograph (SEM) of a neutrophil or macrophage shows immediately that the assumption that these cells are spherical and that their surface area can be calculated easily is incorrect. These cells have numerous surface wrinkles and folds, which means that the actual surface area of these cells is greatly in excess of that of a sphere of the same diameter. A series of elegant biophysical studies about the properties of the neutrophil plasma membrane has been performed using suction of the plasma membrane into micropipettes [7
8
9
]. Their findings show that a moderate amount of suction can expand the membrane into the mouth of the micropipette by up to 5% of the membrane area, and further expansion is possible by applying a greater force. These measurements are consistent with there being a limited amount of "slack" in the wrinkles. Additional force is required to "unwrinkle" the remainder of the membrane, as if the wrinkles are held together by a molecular "velcro-like" mechanism [10
]. Presumably, the "molecular velcro" is sufficiently strong to hold the wrinkles in place against the osmotic pressure tending to swell the cells. However, when neutrophils are activated to expand their plasma membrane, the amount of available slack membrane increases, and the force required to un-velcro the wrinkles is reduced significantly [8
]. As the velcro holding the wrinkles in place has lost its grip under this condition, the membrane in the wrinkles would now become available to accommodate the change in shape as the cell flattens out (Fig. 1)
. The loss of surface wrinkles in neutrophils when they flattened out is apparent in SEMs and can be seen in classic textbooks (Fig. 1b)
. We are now in a position to define the nature of the molecular velcro and suggest how its grip may be loosened.
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THE MOLECULAR VELCRO OF MEMBRANE WRINKLES
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Meandering across the surfaces of myeloid cells, there are linear ridges, projecting 0.8 µm high and 0.1 µm wide, with lengths of 10–15 µm [11
]. These dimensions make them difficult to visualize by standard light microscopy, but they are striking SEM structures (e.g., ref. [12
]). Similarly on lymphocytes, projections from the surface, termed "microvilli," can be seen in transmission electron microscopy images (e.g., ref. [13
]). These wrinkles and microvilli are permanent (or at least long-lived) structures, which influence the distribution of some surface molecules. The distribution of two surface molecules, which are important for leukocyte rolling and adhesion, L-selectin and integrin molecules, containing the ß2-chain (referred to here simply as ß2-integrins), is influenced profoundly by the wrinkles, and selectins are located only on the wrinkles and integrins in the valleys between wrinkles [12
]. The lymphocyte microvilli have parallel actin filaments running within their long axis [13
] to which the cytoplasmic tail of selectins is bound via a linker molecule, ezrin [14
, 15
]. In neutrophils, there is a well-defined cortical network of polymerized actin, but the molecules involved in maintaining the surface wrinkles are not yet fully established but probably include talin. Two general models, however, can be suggested (Fig. 2a
and 2b
), dependent on linkage to the cytoskeleton via ezrin or talin. In both models, a wrinkled membrane could be formed by cross-linking actin to membrane proteins (Fig. 2a
and 2b)
. The two models are not, of course, mutually exclusive, but the "velcro" may be attached to cytoskeleton outside the wrinkles (Fig. 2a)
or within the wrinkle (Fig. 2b)
. These models also depend on the actin-membrane linkage via L-selectin and ß2-integrin and would explain their nonhomogenous distribution on the cell surface, i.e., their exclusion or inclusion from the wrinkled membrane Fig. 2a
and 2b
).
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Figure 2. Release of "wrinkled membrane." The cartoon shows the wrinkles held in place (a) via ß2-integrin/talin/actin linkage and (b) via selectin/ezrin/actin linkage. In the lower cartoons (c and d), the talin and ezrin have been cleaved to release the tension holding the wrinkles in place.
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Ca2+-ACTIVATED RELEASE OF WRINKLED MEMBRANE
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It has been established for over 20 years that a large rise in cytosolic-free Ca2+ accompanies macrophage and neutrophil spreading [16
17
]. It has also been shown that uncaging cytosolic Ca2+ or inositol 1,4,5-trisphosphate (IP3) to provide controlled Ca2+ elevation causes an acceleration in the rate of flattening [19
, 20
]. This is similar to the relationship between Ca2+ and membrane expansion during pseudopod extension around the particle during phagocytosis [21
], where acceleration was dependent on µ-calpain activity [21
, 22
]. This is a Ca2+-activated protease [23
, 24
], which cleaves substrates in vitro and within the cell. The flattening of lymphocytes during adhesion via ß2-integrin is dependent on the activity of calpain [25
, 26
]. As a number of the substrates of calpain are cytoskeletal proteins involved in membrane linkage [27
], this would provide a mechanism for releasing the grip of the molecular velcro. The calpain cleavage site lies between a 4.1/ezrin/radixin/moesin (FERM) domain, binding to membrane-associated proteins, and an actin-binding domain, linking to the cytoskeleton (Fig. 3
). Activation of calpain by Ca2+ would thus lead to the uncoupling of the link between the membrane and the underlying actin cytoskeleton and permit additional membrane to become available for cell flattening (Fig. 2c
and 2d)
. However, for such a proposal to be viable, there must be some selectivity in the activation of calpain, as activation of a (relatively) nonspecific protease within the cytosol of a healthy cell would be disastrous. Also in vitro, activation of µ-calpain requires unusually high Ca2+ concentrations, its dissociation constant is 30 µM [28
], whereas physiological, cytosolic Ca2+ signals reach a maximum of 1 µM. In fact the selectivity may arise from the existence of a subplasma membrane microdomain of high Ca2+. The Ca2+ concentration near the plasma membrane exceeds 50 µM during the influx of Ca2+ from the extracellular medium, although the concentration in the bulk cytosol remains below 1 µM [29
, 30
]. When uncaging Ca2+, it was necessary to elevate bulk, cytosolic-free Ca2+ to levels above the saturation point of the indicator, estimated to be 50 µM [19
]. However, the more physiological signal induced by uncaging IP3 (which induces release of Ca2+ from stores and then physiological Ca2+ influx) induced neutrophil flattening at physiological Ca2+ concentrations in the cytosol [20
]. This again suggests that microdomains exist in the cell, which experiences high Ca2+ during physiological Ca2+ influx. The Ca2+ concentrations within individual wrinkles may reach the highest level, as there is a larger localized surface area to volume ratio. In addition, it has been reported that calpain translocates to the plasma membrane [31
], perhaps by virtue of its C2-like domain. We have found that in the neutrophilic NB4 cell line, elevation of Ca2+ can cause profound and rapid trapping of calpain at the plasma membrane [22
]. Together, these phenomena would limit calpain activity to the strategically required location and target subplasma membrane proteins. It is, in fact, known that cleavage of talin, an important calpain substrate, occurs during physiological Ca2+ influx in neutrophils [32
], suggesting that when activated by Ca2+ influx, calpain-mediated proteolysis has specificity. Furthermore, a number of important calpain substrates, including ezrin, Wiskott-Aldrich syndrome protein, and myosin X, undergo µ-calpain-dependent cleavage in myeloid and lymphoid cells [33
34
35
]. In nonimmune cells, calpains have also been implicated in the local control membrane surface area leading to membrane protrusions [36
]. This proposed mechanism of membrane expansion thus has a number of features, which make this model attractive for explaining the nature of the membrane reservoir and the way in which it is brought into play during leukocyte extravasation
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Figure 3. A stylized view of talin and ezrin showing the locations of the actin binding and FERM domains at separate ends of the molecule with the calpain cleavage site indicated. The FERM domain binds to the cytosolic tail of ß2-integrin and selectin.
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POTENTIAL THERAPEUTIC TARGET
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In this short review, we have identified the need to understand membrane expansion during adhesion and cell flattening of myeloid and lymphoid cells onto the endothelium during extravasation. We have also pointed to an attractive hypothesis as to the nature of this reservoir of additional membrane. Although more work will be required before such a proposal can be fully accepted (or rejected), we hope this article will act as a stimulus to such future work. This mechanism does, however, open an exciting possibility for anti-inflammatory therapy. By targeting inhibition of µ-calpain, it may be possible to slow down or inhibit the influx of immune cells into inflamed sites. As this approach targets a key step in the extravasation process, it would be effective, regardless of the driving stimulus and etiology. It is tantalizing that inhibition of calpain has been shown to reduce inflammatory cell influx effectively in animal models of experimentally induced inflammation and extravasation. For example, inhibition of calpain reduces neutrophil adhesion and improves myocardial dysfunction and inflammation induced by endotoxin in rats [37
] and reduces neutrophil-driven reperfusion injury in the intestine [38
] and kidney [39
]. Animal models of collagen-induced arthritis are potently inhibited by calpain inhibition [40
], and in an experimental model of rheumatoid arthritis induced by antitype collagen mAb, calpain inhibition using the calpain inhibitor, E64d, produced a dramatic reduction in joint inflammation [41
]. Although little mechanistic studies have been performed, it is important to note that E64d is an ester derivation of E64, which is de-esterified intracellularly to generate the calpain inhibitory molecule. As it has no activity on extracellular proteases, this strongly suggests that the important site of calpain activity in this context is within cells rather than as an extracellularly destructive protease. These studies obviously point to calpain as an important target for anti-inflammatory therapy, one that may be the common Achilles’ heel of inflammatory disease.
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ACKNOWLEDGEMENTS
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We thank Chris von Ruhland for the SEMs of neutrophils and the Wellcome Trust (UK) for continued support. We apologize to authors of many of the important publications in this field, which we could not find space to cite or discuss in this short review.
Received November 30, 2006;
revised February 23, 2007;
accepted February 26, 2007.
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ABSTRACT
INTRODUCTION