6. Negrini D and Del Fabbro M. Subatmospheric pressure in the rabbit Valdez L, Sznajder JI, and Selman M.
der JI, and Selman M. Gelatinases A and B are up-regulated
pleural lymphatic network. J Physiol (Lond) 520: 761–769, 1999.
7. Negrini D, Gonano C, and Miserocchi G. Microvascular pressure profile
in intact in situ lung. J Appl Physiol 72: 332–339, 1992.
8. Negrini D, Passi A, De Luca G, and Miserocchi G. Proteoglycan involve-
ment during development of lesional pulmonary edema. Am J Physiol
Lung Cell Mol Physiol 274: L203–L211, 1998.
9. Negrini D, Passi A, De Luca G, and Miserocchi G. Pulmonary interstitial
pressure and proteoglycans during development of pulmonary edema. Am
J Physiol Heart Circ Physiol 270: H2000–H2007, 1996.
10. Nettelblandt O, Tengblad A, and Hällgren R. Lung accumulation of
hyaluronan parallels pulmonary edema in experimental alveolitis. Am J
Physiol Lung Cell Mol Physiol 257: L379–L384, 1989.
11. Pardo A, Barrios R, Maldonado V, Melendez J, Perez J, Ruiz V, Segura-
Brain Glucose Transporters: Relationship to Local
Energy Demand
Roman Duelli and Wolfgang Kuschinsky
Glucose, the major fuel in the brain, is transported across the cell membranes by facilitated diffusion
mediated by glucose transporter proteins. Essentially two types of glucose transporters are localized
in the membranes of brain endothelial cells, astrocytes, and neurons. Their densities are well
adjusted to changes in local energy demand.
T he importance of membrane transport proteins for the ade-
quate supply of the cells with nutrients becomes more and
more evident. In this review, we will focus on the main glucose
transporter proteins in the brain, Glut1 and Glut3. Their expres-
sion and regulation during physiological and pathophysiologi-
cal conditions have recently been extensively analyzed.
Importance of glucose transporters for glucose transport
across cell membranes
Glucose is an essential metabolic substrate of all mam-
malian cells. It is taken up into cells by facilitated diffusion,
which is mediated by members of the glucose transporter
family. Therefore, glucose transporters can be found in the
cell membranes of all mammalian cells. More than any other
organ, the brain is entirely dependent on a continuous sup-
ply of glucose from the circulation since glucose is almost the
sole substrate for energy metabolism. Ketone bodies can be
used as an additional substrate when their plasma concen-
tration is increased. The existence of the blood-brain barrier,
which comprises tight junctions between the endothelial
cells, necessitates the transcellular transport of glucose from
the blood to the brain through the luminal and abluminal
membranes of the brain endothelial cells (2). This transport is
stereospecific for D-glucose. Pharmacological inhibition of
glucose transporter function by substances like phloretin in
R. Duelli and W. Kuschinsky are in the Department of Physiology and Patho-
physiology, University of Heidelberg, Heidelberg, Germany.
0886-1714/99 5.00 © 2001 Int. Union Physiol. Sci./Am.Physiol. Soc.
Downloaded from journals.physiology.org/journal/physiologyonline (179.007.193.099) on July 30, 2020.
in rat lungs by subacute hyperoxia: pathogenetic implications. Am J Pathol
153: 833–844, 1998.
12. Passi A, Negrini D, Albertini R, De Luca G, and Miserocchi G. Involvement
of lung interstitial proteoglycans in development of hydraulic- and elastase-
induced edema. Am J Physiol Lung Cell Mol Physiol 275: L631–L635, 1998.
13. Passi A, Negrini D, Albertini R, Miserocchi G, and De Luca G. The sensi-
tivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9)
and its involvement in the development of hydraulic lung edema. FEBS
Lett 456: 93–96, 1999.
14. Woessner JF. Matrix metalloproteinases and their inhibitors in connective
tissue remodeling. FASEB J 5: 2145–2154, 1991.
15. Zwinkler MP, Iancu D, and Michel RP. Effects of pulmonary fibrosis on the
distribution of edema. Am J Respir Crit Care Med 149: 1276–1285, 1994.
vitro results in a reduction of glucose transfer across brain
cell membranes to <5% of control values, indicating that glu-
cose transporters mediate >95% of the glucose transfer to the
brain. Besides pharmacological inhibition, a defective func-
tion of glucose transporters may also cause a reduced glu-
cose transport to the brain. The defective function of glucose
transporter Glut1 has been demonstrated in infants (14).
Either of two genetic mutations, hemizygosity or nonsense
mutations, results in severe deteriorations of brain metabo-
lism and function. These infants suffer from seizures, delayed
development, and acquired microcephaly. If the disease is
properly diagnosed, the symptoms can be attenuated by a
ketogenic diet that allows, to a certain extent, ketone bodies
to replace glucose as a fuel. These ketone body nutrients are
transported into the cells by specific transport proteins, the
monocarboxylate transporters (MCT).
Glucose transporter isoforms in the different organs
Glucose transporter proteins can be divided into two large
classes, the sodium-dependent and the facilitative glucose
transporters. The sodium-dependent isoforms mediate the
transport of glucose against a concentration gradient. The dri-
ving force is the flux of sodium along an electrochemical gra-
dient that is directed opposite to the transport of glucose.
Such sodium-dependent glucose transporters can be found in
the kidney and other organs. Their existence in the brain has
not been convincingly demonstrated. In contrast to the
sodium-dependent isoforms, the facilitative glucose trans-
porters can only support the flux of glucose along an existing
News Physiol. Sci. • Volume 16 • April 2001 71
 TABLE 1. The facilitative glucose transporter family
joint predecessor may even encompass additional transport
proteins, such as MCTs; glucose transporters and MCTs share
Glut Isoform Tissue Location Comments
a common molecular arrangement in the cell membrane. The
Glut1 Most mammalian cells, 45- and 55-kDa isoforms transport proteins contain 12-membrane-spanning domains,
especially blood-tissue Medium Km value (5–10 mM)
and their COOH terminal and NH2 terminal ends are located
barriers, brain
endothelial cells, on the cytoplasmic side of the cell membrane.
glial cells
Glut2 Liver, pancreas High Km (20–40 mM)
Glut3 Neurons Low Km (1–5 mM) Glucose transporter isoforms in the brain
Glut4 Fat, skeletal muscle, Insulin sensitive
Which types of glucose transporters exist in the brain? Fig-
myocardium
Glut5 Intestine, brain microglia Fructose transporter ure 1 shows the different types. The main glucose transporters
Glut7 Liver Endoplasmic reticulum in the brain are Glut1 and Glut3. Of these, Glut1 exists in two
Km, Michaelis-Menten constant. isoforms of different molecular weights. The 55-kDa isoform is
located at the luminal and the abluminal membranes of the
brain endothelial cells (7), whereas the 45-kDa isoform is
expressed in the perivascular endfeet of the surrounding astro-
concentration gradient for glucose. Among these sodium- cytes (11). The higher molecular weight of the 55-kDa isoform
independent transporters, six functional isoforms have been is due to the existence of a glycosylation site at the first extra-
identified and characterized so far. Their more-or-less organ- cellular loop of the membrane-spanning molecule of Glut1.
specific distribution is outlined in Table 1. Whether this difference in glycosylation between the
The amino acid sequence of each Glut isoform is nearly endothelial and astrocytic isoforms is of functional signifi-
identical when different species are compared. For example, cance is not known. Another feature of Glut1 is its uneven dis-
Glut1 is >95% identical between different mammalian species tribution between the cytoplasm and the luminal and the
(10). In addition to the high conservation of each Glut isoform abluminal membranes of the endothelial cells, as demon-
during evolution, comparing the amino acid sequence of the strated by electron microscopy. The fractional distribution of
six glucose transporter isoforms seems to indicate that all glu- Glut1 to the cytoplasm and to the cell membranes of the
cose transporters originated from a joint predecessor. An iden- endothelial cells is shown schematically in Fig. 2 (1, 7).
tity of 39-65% can be found within a given species. Such a Although the fractional distribution varies between different

FIGURE 1. Location of the different glucose transporter isoforms in the brain. Glut1 is abundant in its 55-kDa isoform in the endothelial cells, whereas the 45-
kDa isoform is expressed in astrocytes. Glut3 is the neuronal glucose transporter. Only traces of other Glut isoforms are found in the brain; of these, Glut4 has
been detected in distinct neuronal populations and Glut5 in microglia.

72 News Physiol. Sci. • Volume 16 • April 2001

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FIGURE 2. Cellular distribution of Glut1 in the luminal and abluminal membranes of brain endothelial cells. Although differences exist between species, the small-
est fraction of Glut1 is generally found in the cytoplasm and the largest fraction at the abluminal membrane. The lower Glut1 content at the luminal membrane
may be due to the comparably high glucose concentration at this membrane, which is close to the plasma concentration.
species, the lowest density of Glut1 molecules is preferentially
found in the cytoplasm and the highest density in the ablumi-
nal membrane. Whether this fractional distribution of Glut1 in
the brain is fixed over longer time periods or whether these
glucose transporters can be redistributed between the cyto-
plasm and the abluminal or luminal membranes is not known.
An acute redistribution of glucose transporters within the cell
has been found for Glut4 in skeletal muscle and fat tissue
under the influence of insulin. Besides the two Glut1 iso-
forms, Glut3 is of major importance for the transport of glu-
cose within the brain. The low Michaelis-Menten constant
value of Glut3 facilitates a continuous supply of glucose to the
neurons even at low interstitial glucose concentrations. Traces
of other isoforms of glucose transporters could be detected in
specific brain cells. Of these isoforms, Glut5 fructose trans-
porters have been detected in brain microglia and Glut4 glu-
cose transporters in specific neuronal cell populations. The
regional distribution pattern of Glut4 in the brain appears to
correspond to that of insulin receptors and of insulin-contain-
ing cells, indicating the possibility of Glut4 regulation by
insulin in the brain as well. Recently, a novel glucose trans-
porter has been described and has been named GlutX1 (8).
Glucose transporters of the type GlutX1 have only one-third
homology with Glut1–5. GlutX1 mRNA has been detected in
several brain structures and some other organs, like testis,
adrenal gland, liver, and lung.
Heterogeneous distribution of glucose transporters in
the brain
The brain is a heterogeneous organ with respect to cell
density and functional activation. Does this heterogeneity
also apply for the distribution of glucose transporters? A
method was developed that allows us to detect the distribu-
tion of Glut1 and Glut3 densities in different brain regions.
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Using antibodies and autoradiography, local heterogeneities
could be found for Glut1 and Glut3. The concentrations var-
ied by a factor of two for both Glut1 and Glut3. Thus the
autoradiographic techniques have shown a heterogeneous
distribution of Glut1 and Glut3 in the brain.
Correlation between glucose transporter densities and
capillary density
What could be the cause of the heterogeneous distribution
of glucose transporters in the brain? Two possibilities should
be considered. One possibility is that the density of glucose
transporters reflects the distribution of capillaries. An uneven
distribution of capillary densities was found in the brain dur-
ing previous studies by our group. Capillary densities of dif-
ferent brain structures are directly related to their local blood
flow. Brain structures in which resting blood flow is high have
a high capillary density and vice versa. Thus the morpholog-
ical basis of the different flow values in different brain struc-
tures is the amount of perfused capillaries per volume of
brain tissue. This direct relationship between blood flow and
capillary morphology is based on a continuous perfusion of
capillaries under normal conditions. In contrast to previous
assumptions of nonperfused capillaries and capillary recruit-
ment, it is now generally accepted that all capillaries are per-
fused in the brain under normal, nonischemic conditions,
although at different velocities. Therefore, glucose is taken up
from all capillaries by the glucose transporters. Glucose
transporters are associated with blood vessels since Glut1 is
located in the capillary wall (55-kDa isoform) and close to
capillaries (45-kDa isoform). Comparison of Glut1 density
and capillary density shows a close correlation between local
Glut1 density and local capillary density when plotted for the
different brain structures. Thus capillary density is a major
determinant of Glut1 density in the brain.
News Physiol. Sci. • Volume 16 • April 2001 73

FIGURE 3. Correlation between glucose transporter densities and local cere-
bral glucose utilization. A close correlation (r = 0.78, P < 0.01) between both
glucose transporter isoforms and the local cerebral glucose utilization can be
demonstrated.
Correlation between local glucose transporter densities
and local cerebral glucose utilization
As a second possibility, the heterogeneous distribution of
glucose transporters in the brain could be related to the local
glucose utilization. In this case, the different rates of glucose
utilization in different brain structures would be reflected in
differing densities of Glut1 and Glut3. This possibility was
tested by using immunoautoradiography to detect Glut1 or
Glut3 and the 2-[14C]deoxyglucose method to determine local
cerebral glucose utilization. For different brain structures, the
local values of glucose utilization were related to the local dis-
tribution of the glucose transporter proteins Glut1 and Glut3.
A positive correlation could be shown between the local
densities of Glut1 and local cerebral glucose utilization as
well as the local densities of Glut3 and local cerebral glucose
utilization, as shown in Fig. 3 (5). The most likely explanation
for these results is that the local cerebral glucose utilization
determines the local densities of both glucose transporters,
Glut1 and Glut3. In addition, the local cerebral glucose uti-
lization also determines the local capillary densities in the
different brain structures. The stimulus for the varying expres-
sion of glucose transporters is not known. Besides the local
glucose utilization, the local oxygen consumption in the dif-
ferent brain structures may be relevant. Because of the normally
fixed stoichiometric relationship between oxygen consump-
tion and glucose utilization (6 mol oxygen/1 mol glucose), it
is not possible to differentiate between the impact that each
of these two parameters has as a local stimulus of glucose
transporter expression.
Regulation of glucose transporter expression in the
brain: chronic activation
The correlations between the local densities of Glut1 or
Glut3 and local cerebral glucose utilization had been deter-
mined in rats under normal experimental conditions. The cor-
relations indicate that the densities of glucose transporters
74 News Physiol. Sci. • Volume 16 • April 2001
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apparently have been adjusted to the local metabolic
demand of the different brain structures. The time course of
this long term adjustment was investigated by using several
types of experiments in which either the local metabolic
rate for glucose or the plasma glucose concentration was
changed over several days. To stimulate various brain regions
chronically, rats obtained a continuous infusion of a nicotine
solution for 1 wk. Under these conditions, local glucose uti-
lization is chronically increased in specific brain structures.
Moreover, glucose transporter densities of Glut1 and Glut3
showed a distinct increase only in brain structures with an
elevated local cerebral glucose utilization. Thus the density
of glucose transporters can be chronically raised in specific
brain regions as a response to an enhanced metabolic rate for
glucose. The increase in the local densities of glucose trans-
porters (mean +19%) is paralleled by an increase in local
cerebral glucose utilization (mean +15%). The close correla-
tion between Glut1 or Glut3 densities and local cerebral glu-
cose utilization shown for control conditions was maintained
during nicotine infusion (6).
Additional local activation studies confirmed these con-
clusions. In these studies, rats were water deprived for 3 days
to stimulate the osmoregulatory system of the brain. Under
these conditions, the densities of glucose transporters Glut1
and Glut3 increased in parallel to the increased local cere-
bral glucose utilization in some of the osmoregulatory struc-
tures. In this case, the increase in the transporter densities in
these structures (mean Glut1 +26%, mean Glut3 +39%) was
lower than the increase in local cerebral glucose utilization
(mean +85%). Both types of studies, nicotine infusion and
water deprivation (3), as well as studies by Vannucci et al.
(17), indicate a moderate long term local upregulation of
glucose transporters as a response to increased local cere-
bral glucose utilization.
Regulation of glucose transporter expression in the
brain: chronic inactivation
Whereas these experiments had shown an upregulation of
glucose transporters, it remained to be shown whether a
chronic decrease in glucose utilization in specific brain struc-
tures is followed by a selective decrease of glucose trans-
porter densities. The visual system was chosen as an example
of a chronic deprivation of a functional system in the brain.
Unilateral visual deprivation was induced by monocular enu-
cleation in rats. After 1 wk, the contralateral structures of the
visual system were analyzed for the densities of glucose
transporters Glut1 and Glut3 and for local cerebral glucose
utilization. Since >90% of the afferent fibers from the retina
cross in the chiasma in the rat, the ipsilateral structures of the
visual system served as controls. During chronic visual depri-
vation, Glut1 and Glut3 densities and local cerebral glucose
utilization were moderately decreased in some structures of
the visual system (mean Glut1 –1%, mean Glut3 –7%, mean
local cerebral glucose utilization –14%). Primary visual
structures receiving direct retinal projections (dorsal lateral
geniculate nucleus, superior colliculus layer I-III) were more
affected than secondary structures that receive no direct
retinal input (e.g., visual cortex). Thus glucose transporters
can be moderately downregulated as a consequence of a
lowered metabolic rate for glucose (4).
Regulation of glucose transporter expression in the
brain: chronic hypoglycemia
Another approach to the question of whether glucose trans-
porters can be up- and downregulated is to measure the den-
sities of glucose transporters during chronic changes in the
plasma glucose concentration. Under these conditions, a more
general increase or decrease of glucose transporter densities
can be expected, if there is an effect at all. Therefore, chronic
hypo- and hyperglycemia were tested. During chronic hypo-
glycemia, induced by a continuous infusion of insulin into rats
for 1 wk, the mean density of Glut1 remained unchanged,
whereas the mean density of Glut3 increased slightly, although
significantly (+3%). A previous study of Uehara et al. (15), in
which the quantitative immunoblot technique was used, had
qualitatively but not quantitatively (+76%) the same result. To
determine whether the increased density of Glut3 is related to
a change in glucose metabolism, cerebral glucose utilization
was quantified by the 2-deoxyglucose method. Mean glucose
utilization was decreased by 15%. Local analysis of transporter
densities (Glut1 and Glut3) and glucose utilization showed a
significant correlation between local glucose transporter den-
sities (Glut1 and Glut3) and local cerebral glucose utilization
during hypoglycemia, as previously observed during normo-
glycemia. Therefore, 1 wk of hypoglycemia is a stimulus for the
moderate induction of additional Glut3 in the brain. These
additional neuronal glucose transporters may support the main-
tenance of glucose utilization even though glucose utilization
remains decreased (5).
Regulation of glucose transporter expression in the
brain: chronic hyperglycemia
Chronic hyperglycemia was induced for 3 wk by selective
pharmacological destruction of pancreatic β-cells with strep-
tozotocin. As a result, a moderate decrease of Glut1 (–8%)
was measured, whereas Glut3 remained unchanged. In
accordance with these findings, Pardridge et al. (12) found a
downregulation of Glut1 after 1 wk of diabetes in a cerebral
microvessel preparation that only contained the vascular
Glut1. Thus chronic hyperglycemia is a stimulus for a mod-
erate downregulation of Glut1.
Developmental regulation of glucose transporters
In the brain, glucose transporter densities are regulated dur-
ing development. Whereas Glut1 already exists at the blood-
brain barrier at birth in rats, its density increases rapidly
between 10 and 20 days after birth, indicating the maturation
of the blood-brain barrier during that period. Thirty days after
birth, adult Glut1 levels are reached (18). Accordingly, the
maturation of the blood-brain barrier is paralleled by the neu-
ronal maturation, including a developmental increase of the
neuronal glucose transporter Glut3. The most prominent
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increase of Glut3 density occurs between days 14 and 21. At
day 30, ~90% of adult Glut3 levels are attained (16).
Mechanisms of glucose transporter regulation
The regulation of glucose transporter expression appears to
occur at the transcriptional, posttranscriptional, and post-
translational levels. The genomic sequence of Glut1 consists
of ~35,000 base pairs, of which the promotor region contains
several elements for transcription factors. For an example of
transcriptional control, Glut1 mRNA is increased during
hypoxia. On the posttranscriptional level, glucose transporter
density can be modified through regulation of the cellular
content of transporter protein by alteration of transcript stabil-
ity (13). Regulated Glut1 mRNA decay plays an important role
in control of posttranscriptional gene expression. An essential
element in this regulation is the 3-untranslated region of the
message. Alterations of the 3-untranslated region by specific
proteins can modify the transcript stability. For an example of
translational regulation, insulin specifically upregulates Glut1
mRNA translation. An additional regulatory mechanism exists
for Glut3; an increase in Glut3 can occur by a mechanism not
affecting transcription or translation of new Glut3 protein but
rather by stabilization of the protein, thus prolonging the half-
life of Glut3 protein during an increased glucose demand (9).
Due to an increased half-life of Glut3 at an unchanged syn-
thesis rate, total Glut3 is then elevated.
Conclusion
The spatial heterogeneity of energy metabolism in the
brain results in spatial heterogeneities of capillary density
and glucose transporter density. The long term demand for
glucose in each brain structure determines its glucose trans-
porter density. Chronic changes in the local or global energy
metabolism of the brain are followed by moderate changes in
the glucose transporter densities, resulting in the support of
energy metabolism.
Our work was supported by the Deutsche Forschungsgemeinschaft, Bonn,
Germany, the Forschungsförderung of the University of Heidelberg, Heidelberg,
Germany, and VERUM, Stiftung für Verhalten und Umwelt, Munich, Germany.
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Leukocyte Recruitment in the Microcirculation:
the Rolling Paradigm Revisited
Paul Kubes and Steven M. Kerfoot
Intravital microscopy has done much to elucidate the cascade of events involved in the recruitment
of leukocytes to sites of inflammation. Here we review the physiological relevance of leukocyte
rolling and some of the important subtleties of this process, highlighting limitations in our
knowledge and directions for future investigation.
F ighter planes landing on an aircraft carrier are brought from
a high speed to a stop very quickly by catching onto cables
strung across the flight deck. Similarly, a leukocyte moving at
very high speeds in the mainstream of blood must also tether
to and roll along the vessel wall before adhering at a site of
injury and/or inflammation. Although the phenomenon of
tethering/rolling was certainly described more than 100 years
ago by Cohnheim (3), the molecular mechanisms have only
been studied extensively in the last decade. Two key observa-
tions sparked extensive interest in the study of leukocyte
rolling. First, inhibiting leukocyte adhesion did not reduce
leukocyte rolling, raising the possibility that rolling and adhe-
sion were two distinct molecular events (1). Second, inhibit-
ing rolling reduced adhesion, suggesting that rolling was a
prerequisite of leukocyte adhesion/recruitment and ultimately
the inflammatory response (20).
The ability to visualize the microcirculation has played an
essential role in our study of the importance of rolling in the
recruitment process. Nevertheless, important issues remain
unanswered for physiologists studying the microcirculation,
P. Kubes and S. M. Kerfoot are in the Immunology Research Group, Depart-
ment of Physiology and Biophysics, University of Calgary, Calgary, AB,
Canada T2N 4N1.
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15. Uehara Y, Nipper V, and McCall AL. Chronic insulin hypoglycemia
induces GLUT-3 protein in rat brain neurons. Am J Physiol Endocrinol
Metab 272: E716–E719, 1997.
16. Vannucci SJ. Developmental expression of GLUT1 and GLUT3 glucose
transporters in rat brain. J Neurochem 62: 240–246, 1994.
17. Vannucci SJ, Maher F, Koehler E, and Simpson IA. Altered expression of
GLUT-1 and GLUT-3 glucose transporters in neurohypophysis of water-
deprived or diabetic rats. Am J Physiol Endocrinol Metab 267:
E605–E611, 1994.
18. Zeller K, Vogel J, and Kuschinsky W. Postnatal distribution of Glut1 glu-
cose transporter and relative capillary density in blood-brain barrier struc-
tures and circumventricular organs during development. Dev Brain Res
91: 200–208, 1996.
mainly because of technical limitations. In this brief
overview, we first summarize our current understanding of
the physiological importance of leukocyte rolling and how
this event may impact on inflammatory cell recruitment. We
also highlight technical limitations and areas that clearly
require further investigation.
Leukocyte recruitment cascade
Figure 1 is a representative illustration of the type found in
most immunology textbooks depicting the universal or unify-
ing theme of leukocyte recruitment from the vasculature into
tissues. The basic premise is that leukocyte recruitment occurs
within postcapillary venules and is dependent on a cascade of
events involving the selectins as the primary molecules that
induce and support rolling. Chemokines, lipid mediators, and
other proinflammatory molecules presented on the surface of
the endothelium then activate a second family of adhesion
molecules, the integrins, and cause cells to firmly adhere. It is
now well appreciated that α4-integrin is an exception to this
rule in that this molecule can mediate both rolling and adhe-
sion. Once adherent, leukocytes can then migrate out of the
vasculature. The fact that this is an interdependent series of
events has been nicely illustrated in vitro by Lawrence and
Springer (13). Under flow conditions in the absence of
0886-1714/99 5.00 © 2001 Int. Union Physiol. Sci./Am.Physiol. Soc.