00:00
Okay, so we've had that
initial trigger,
and we've released the molecules,
that's what's down
in that lower right hand corner
macrophages and mast cells,
and other cells
in that extravascular space
are releasing mediators
that tell the endothelium,
gets sticky.
00:18
So they're also telling
the endothelium, be leaky.
00:22
As a result of that,
we now have a sticky surface,
and the leukocytes
are able to bounce
over the surface of that,
and it will begin to bind
to molecules called selectins.
00:35
That's on the next slide.
00:37
So this rolling involves selectins.
00:39
That's actually a good name
for a molecule.
00:41
It's a selective lectin.
00:43
Meaning that it selectively
binds certain sugars.
00:46
So on the bottom,
you see it's an endothelial cell
and sticking up from that
is a protein called a selectin.
00:53
and there are various
kinds of selectins,
we'll talk about briefly.
00:56
It sticks up above
the glycocalyx.
00:59
So it's well into the bloodstream.
01:01
And on the end, is a little receptor
that will bind sugars.
01:05
And it tends to bind
a complex of sugars,
not just one kind of sugar.
01:10
The most common sugar complex
it's bound is called Sialyl-Lewis X.
01:15
And it involves at least
four different sugar groups
a fucose, and an
N-acetyl glucosamine,
a galactose,
and an N-acetylneuraminic acid.
01:25
Details?
Not too important.
01:27
But that's what those different
things mean in the green balls.
01:31
Those are on the surface of various
glycoproteins on the neutrophil.
01:35
And so when you have selectins
that have been activated,
making the endothelium sticky,
now the neutrophils
bouncing over the surface
will be able to bind to those.
01:45
So more words about selectins.
01:48
It's a lectin-like binding domain,
it binds to carbohydrates.
01:52
That's why it's called a
selective lectin. A selectin.
01:55
There are three members.
01:56
So there is E-selectin,
that's on endothelial cells.
01:59
Easy to remember,
E-selectin on endothelial cells.
02:03
It binds that Sialyl-Lewis X.
02:06
There is P-selectin. It was
originally described on platelets.
02:09
That's why it's called P-selectin
but it's also an endothelial cells.
02:13
And it also binds Sialyl-Lewis X.
02:16
And then, in the same way
that we have selectin
that are in endothelial cells,
we can also have selectins
that are expressed on the leukocyte
that bind sugars
present on the endothelium.
02:28
Okay, pretty straightforward.
02:29
And you don't need to know
the names,
but they're there
for your reference.
02:33
How do we regulate
the expression of the selectins?
Well, one, the L-selectin,
that lectin binding protein
that's on leukocytes,
is constitutively expressed.
02:44
It's always there
at a low level.
02:47
It makes the leukocyte stick until
they start bouncing over the surface
of the endothelium and rolling.
02:53
So we can have them expressed
at a low level all the time.
02:59
We can redistribute from
intracellular stores, P-selectin.
03:05
So the way that we regulate
P-selectin expression,
it's always sitting
inside an endothelial cell,
ready to go.
03:12
But until we signal it,
until we stimulate that cell
with certain mediators
coming from the mast cells
in the macrophages,
they don't move it
from the inside to the outside.
03:22
But the minute they get stimulated,
they move it out to the surface,
and now that endothelial cell
will become sticky
because of the expression
of the P-selectin.
03:33
We can also have various
inflammatory mediators
that drive endothelial expression
of new selectins.
03:40
So, E-selectin is actually driven by
inflammatory mediators
like Tumor Necrosis Factor,
that's TNF, or interleukin-1.
03:49
So the cell doesn't make it until we
stimulate it with inflammation.
03:54
So those are different ways that
we can keep cells from sticking
until we're ready.
04:01
That Selectin-mediated Rolling.
04:03
Here, the cells are going from
left to right
moving along here.
04:08
The selectins and the binding sites,
the receptors
are at the very tip
of the leukocyte.
04:16
So leukocyte is not a round ball.
It's not a smooth ball.
04:19
It's more like a sea urchin
with lots of little spikes
all the way around it.
04:24
And on the tips of that
are the receptors,
the sugar expression,
the Sialyl-Lewis X,
that will bind to the selectin
that's been expressed
on the endothelium.
04:35
So the receptors expressed
to the microvilli tip.
04:38
It's a very
low-affinity interaction,
and allows the cells to roll.
04:42
And they stick
and then they release.
04:44
And they stick
and then they release.
04:46
It's a very fast
on and off rate.
04:47
The shear forces
because they're shear
going from left to right,
constantly rolling the cell.
04:54
So it may take a while
before they get to firm adhesion.
04:57
And we get repetitive
attachment and detachment.
05:00
Okay.
So that's how you get rolling.