It’s no good simply recognizing
that there’s a threat.
The cells of the immune response
need to respond to that threat.
This is where signaling is required
so that genes in the nucleus of the
immune system cell become activated
in order to initiate the response.
Looking at an example of a cell surface Pattern
Recognition Receptor, here you can see on the surface of
this immune system cell, Pattern Recognition Receptor
which is associated with a molecule called MyD88.
Following recognition of a PAMP by the
Pattern Recognition Receptor, a signal
is initiated which involves several different
molecules- IRAK, TRAF6, TAK1, IKK.
And the consequence of this recognition
and signaling event is that the molecule
IKK phosphorylates a molecule called
IKB, which is the inhibitor of NFkB.
NFkB is a transcription factor.
Transcription factors bind
to genes in the nucleus.
But NFkB in this diagram, you will see is not present
in the nucleus, it’s present in the cytoplasm.
And the reason that it’s in the cytoplasm is its
being held there by the inhibitor of NFkB, IkB.
And IKK is a kinase, an
enzyme that phosphorylates IkB.
And when IkB becomes phosphorylated,
it ends up being degraded,
and that means that it releases the NFkB
from being held in the cytoplasm.
And the NFkB can then translocate into the
nucleus and initiate gene transcription.
And multiples genes will be activated
as a consequence of recognition of
Pathogen-Associated Molecular Patterns
by the Pattern Recognition Receptor.
These will include genes for cytokines, for antimicrobial
molecules, and for various adhesion molecules that are
required for cells of the immune response to leave the
blood circulation and get into the site of the infection.
Following activation of these genes subsequent to
recognition of Pathogen-Associated Molecular Patterns by the
Pattern Recognition Receptor, there needs to be the
generation of structures that are called inflammasomes.
As you can see, following gene transcription
in this particular example, the preliminary
forms of two cytokines have been produced,
Pro-Interleukin-1β and Pro-Interleukin-18.
These are precursors of the
active form of these cytokines.
But in order to activate them, we need to
generate this structure called the inflammasome.
The inflammasome is generated just like the
signaling, initially we saw through the
Pattern Recognition Receptor, that the inflammasome is
generated following recognition of PAMPs and DAMPs.
There are in fact several
different types of inflammasome.
We’re going to look at
the NLRP3 inflammasome.
So this molecule, NLRP3 becomes
associated with two other molecules,
one of which is called ASC and the
other of which is Pro-caspase-1.
And following signaling through Pattern Recognition
Receptors and other signaling events
that occur following encounter with DAMPs or PAMPs,
this structure, the inflammasome is generated.
And the purpose of this structure is to
activate Pro-caspase-1 into an active caspase-1.
And this active caspase-1 is now able to
activate Pro-IL-1 and Pro-IL-18 to produce
the active forms of these two cytokines
- Interleukin-1β and Interleukin-18.
And these cytokines, belong to a group of
cytokines that we call pro-inflammatory cytokines.
They help generate inflammation.
So following the conversion of Pro-IL-1β and
Pro-IL-18 into their active forms, these two
pro-inflammatory cytokines will be released from
the cells and help to mediate inflammation.
Hence the name, the inflammasome.