Well, that's a lot of questions that are still being worked out. The pathway has not been known long enough, we still only have the basic outlines of how things work, but the more that is discovered, the more obvious it is becoming that this is one ancient, fundamentally important signaling mechanism that has its fingers in just about everything, directly or indirectly.
Using TLR agonists is not necessarily dangerous, and in many cases can be very therapeutic. An example is the use of adjuvants, which have been around for a very long time. These things facilitate vaccines, and often vaccines will not work without adjuvants. Nobody knew how adjuvants worked until fairly recently, and now it turns out that many of them are TLR agonists.
With regards to "broadly affecting a pathway".... well, I don't see this as a problem, because the pathway has so many combinatorial options, and also because the pathway is probably very flexible and probably has a significant measure of redundancy (how much is not at all clear yet). TLRs respond to only limited sets of molecules, first of all; a TLR4 agonist will do nothing to TLR9, for example. Then, it turns out that the response from there is quite complex. TLRs assemble into heteromeric complexes on the cell surface, but also in the endosomes and phagosomes. The interactions may or may not be cooperative. Some TLRs are expressed only at the cell surface, and others are never expressed at the cell surface. As you might guess, TLRs that detect viral-derived molecules are never found at the cell surface, which makes sense.
From there, the downstream network is already very complex, and has not been worked out in any detail yet. TLRs may or may not activate NF-kB, may or may not get routed through the IRF3/IFN pathway, may activate NF-kB circuitously and indirectly, may proceed through at least 3 arms of the MAPK network, can involve the JAK/STAT pathways, etc. etc. etc.
And that doesn't even consider the regulation, which is multilayered, and there also seems to be a lot of bi-directional crosstalk that is currently being worked out. Regulation occurs via phosphorylation/dephosphorylation events, but also ubiquitination/deubiquitination and sumoylation/desumoylation, and all these modifications are generally inputted from other pathways.
So, I would characterize the whole network as being less linear and hardwired, much more malleable and tunable, and capable of responding to perturbations.
Based on these kinds of considerations, you can appreciate why "broadly affecting" the TLR pathway is difficult or impossible to do. But you can also see that targeting the pathway to produce a given response will not be a simple matter because the network is so complex. It is hard to know what your intervention will do ahead of time; much of it will just have to be determined empirically.
Hope this helps,
T |
