The phagocytic cells are predominantly
the neutrophils and the macrophages.
Neutrophils are fairly short lived.
They have a half life
of two to three days.
They travel around the blood, but they will leave
the blood if there's an infection in the tissues.
Monocytes are relatively
longer lived cells.
They also circulate around in the blood and they will also
leave the blood if there's an infection in the tissues.
But when they leave the blood, they further differentiate
into macrophages, and these are relatively long lived cells.
So neutrophils, whether they're in the blood or
the tissues they're referred to as neutrophils,
whereas the blood monocyte further differentiates
or develops into the tissue macrophage.
In order for the blood neutrophil and the blood
monocyte to exit from the blood vessel and
enter the tissues, they need to bind to the blood
vessel endothelium using adhesion molecules.
They will then squeeze through the gaps between
the blood vessel endothelial cells and be
attracted into the site of the infection by a
concentration gradient of chemotactic factors.
The phagocytic cells use pattern
recognition receptors to recognize
pathogen-associated molecular patterns
on the surface of microorganisms.
The pathogen can also be coated with
substances, we refer to these substances
as opsonins that are additionally
recognized by the phagocytic cell.
This helps facilitate the binding of
the microorganism to the phagocyte.
There are several different
substances that can act as opsonins.
So for example, both the neutrophil and the
macrophage have on their cell surface, as well
as many, many, many other molecules, they have complement
receptors that can recognize complement.
So the microorganisms can be coated
with complement, and this complement
coating of the microorganism is
recognized by the complement receptors.
In other words, complement is
acting as an opsonin to facilitate
binding and subsequent phagocytosis of the microorganism.
Another molecule on the surface of both neutrophils
and macrophages are so called Fc receptors.
These receptors recognize the Fc
part of the antibody molecule.
So antibodies that recognize antigens
on the surface of the microorganisms can
coat the microorganism, and again act
as opsonins to facilitate phagocytosis.
Once engulfed by the phagocytic cell, the pathogen
is destroyed using reactive oxygen intermediates that
are generated by a respiratory burst and also by a
number of non-oxygen dependent killing mechanisms.
So let's have a look at that process
in a little bit more detail.
Pattern Recognition Receptor on the surface
of the phagocyte will recognize PAMPs
(pathogen-associated molecular patterns)
on the surface of the microorganism.
Additionally, the microorganism may be
opsonized with complement or antibody.
So, following this initial binding, the phagocyte
then puts its membrane around the microbe.
It zips up around the microorganism
to enclose the microorganism.
The microorganism is now trapped within the phagocyte,
within a vesicle that is referred to as a phagosome.
Within the microorganisms, there are other
vesicles that are referred to as lysosomes.
And these contain toxic molecules and enzymes
that are going to destroy the engulfed pathogen.
So what needs to happen now, is the
lysosome needs to fuse with the phagosome.
And the fusion of the lysosome with the phagosome
containing the trapped microorganism generates a
structure that is referred to as a phagolysosome,
the combination of the phagosome and the lysosome.
There are then various
enzymes that are activated.
For example, the phagocyte oxidase
which will generate from molecular
oxygen, reactive oxygen species that
can be used to kill the microorganism.
And also, INOS (inducible nitric oxide synthase)
which uses arginine to produce nitric oxide (NO).
As a by-product of that enzymatic
reaction, citrulline will be produced.
So, killing of the microbes by reactive oxygen
Species, by nitric oxide and also by lysosomal
enzymes in the phagolysosome will ensure the
destruction of the engulfed microorganism.
There are a whole variety of substances
that are produced by phagocytic
cells, which leave the microorganism
with very little chance of survival.
In fact some microorganisms have evolved
mechanisms to avoid these killing processes.
But most will be defeated by them.
There are a group of mechanisms that collectively
require molecular oxygen for their generation.
And therefore, we refer to these as the oxygen
dependent mechanisms of micro-killing by the phagocyte.
These include superoxide, singlet oxygen, the hydroxyl
radical, hydrogen peroxide, hypochlorite and nitric oxide.
In addition to these oxygen dependent mechanisms, there
are a whole variety of oxygen independent mechanisms.
Just four of them are shown here.
Lysozyme is an enzyme that cleaves
peptidoglycan in bacterial cell walls.
Defensins which form channels
in bacterial membranes.
Lactoferrin which is a very interesting
molecule, it chelates iron.
It removes iron from the immediate
environment of the microorganism.
And iron is an essential
nutrient for bacteria.
And proteases, such as elastase
which again can attack bacteria.
In addition, neutrophils can extrude
their DNA and their granule contents
to produce what are called neutrophil
extracellular traps or NETs.
And these contain lysozyme,
elastase, defensins, etc, etc.
Molecules that are microbicidal.
So as well as engulfing microorganisms, and killing the
microorganisms within the phagocytic cell, the phagocytes,
particularly the neutrophils can release substances to the
outside that will kill microorganisms in the immediate vicinity.