Inflammation gets a pretty bad rap these days, but in general your body actually intends inflammation to be helpful. In general, inflammation is supposed to be a healthy, defensive response to potentially harmful things, like invading viruses and bacteria, or irritants. It’s only when the balance of inflammation is off, that problems occur. For example, if you have insufficient inflammation, pathogens (i.e. bad bugs) can take advantage of this too little or too late immune response to hijack your cells. On the other hand, if you have too much inflammation, this can lead to chronic problems like IBD (inflammatory bowel disease) or autoimmunity.
Last week, we learned about a type of cell in your gut that helps sense what’s going on in your intestines, and provide a good, balanced immune response to the microbes hanging out in there. This week, we are going to dive a little deeper into balancing out immune responses, and get molecular (really, REALLY small). If we go even smaller than the cell, what can we find there that helps our body achieve this balance?
Today, we’re going to focus in on one of many different and interconnected systems within human cells which help keep track of all the things going on in your body, and then decide whether or not inflammation is needed. For today, I took a very scientific approach in choosing which cellular machine to focus on: I chose the one with the coolest name.
Today, I present to you (drumroll, please)….
Cool name, right? But what exactly are they?
Inflammasomes are elegant cellular machines that are made up of several different individual proteins. As we’ve discussed before on Microbial Mondays, when you take a more molecular or microscopic point of view, you can think of each cell (whether it's human, bacterial, or otherwise) as a factory, and proteins as the workers and machines inside that factory. Proteins aren’t just things you find in meat or beans or weird vanilla-flavoured workout powders. From the molecular viewpoint, proteins are actually perhaps the most dynamic, machine-like molecules there are. As you can see from the inflammasome comic above, they can take on some pretty neat shapes to form their function. I indeed took some liberty in adding a superman cape and a smile, but inflammasomes really do have that characteristic helicopter-like structure.
So, we know so far that inflammasomes are machines made up of a few different, individual types of proteins. What brings all these different proteins together, though?
The proteins that make up inflammasomes start to assemble after the cell senses one of two different kinds of danger signals. The two possible kinds of danger signals are from either 1) microbes invading, or 2) damage to the cell. That damage to the cell might also be connected to microbes invading, but it could also be more physical damage – like a papercut or a wooden sliver that pokes into your skin and slices through cells. If you’re super keen, you might also remember from last week that cells can also be damaged when the delicate balance of inflammation gets upset. Inflammasomes can also sense this damage, meaning that they can help contribute to that “downward spiral of inflammation” that we see in chronic inflammatory diseases like IBD.
Once inflammasomes have sensed one of these danger signals, they are activated. Time to move on to the next step: sending out a signal to other cells that something is wrong!
The inflammasome itself will get to work at pumping out messages that can be sent to other cells in your body to come and help clean up the localized mess. These messages, called cytokines, are kind of like letters addressed to immune cells, which then come back to the source of the initial messenger. The immune cells will find their way back towards the original cells containing activated inflammasomes. However, by the time they get there, they will probably not be able to find that original cell.
Why? The last action of inflammasomes is to coordinate a carefully organized suicide by the cell that it is inside. Huh? Why would the inflammasome do that? This reaction is actually mostly useful for the first kind of danger signal, i.e. invading microbes. If the inflammasome had sensed that viruses or bacteria had hijacked its cell, then it’s actually a pretty smart idea to blow up the cell. If you blow up a factory when you sense that dangerous intruders have hijacked it, the intruders won’t be able to use all the machines in that factory for their nefarious purposes. On top of that, the inflammasome will have already helped send out messages to far-off immune cells to come and destroy the microbial intruders. Problem solved!
However, if the inflammasome sensed the second kind of danger signal, i.e. damage to the cell, sometimes things can go wrong.
In the best case scenario, the damaged cell will send out messages to immune cells saying, “clean up my mess!”, and then proceed to die. The immune cells can then go on janitorial duty, eat up the exploded cell goop, and life will carry on as normal.
In the worst case scenario, the damaged cell will send out the same “clean up my mess!” message to immune cells before dying, but the immune cells will become confused upon arrival. The immune cells will indeed start cleaning up the mess of the dead cell, but they won’t be able to find the cause of the original danger signal, like they would if the initial problem had been a bacterial invader. They will keep searching, and start to send “help me!” messages to more immune cells. More and more immune cells will come into the area, searching for the problem, and killing healthy cells as they look. This mess of immune cells searching for a problem and not finding it thus becomes a problem itself. This particular immune cell mess is part of what we call chronic inflammation.
We probably have this system, which works very well for infectious disease, but not so well in terms of excessive inflammation, because on an evolutionary time scale, microbes were by far the biggest threat to the human immune system. We definitely had a lot of infectious disease going around, and we didn’t tend to live long enough to have problems with chronic inflammatory diseases like Alzheimer’s or IBD. As a species, we humans and our inflammasomes grew up mainly responding to danger signal #1: invading microbes.
Nowadays, we are lucky enough to live in a world with vaccines and antibiotics, and we don’t have to worry quite as much about signal #1. Vaccines and antibiotics are immunological superheros: they help us fight off diseases that our own immune systems would struggle to evade without help. Now, we live longer, easier lives, and signal #2, damage to the cell, has become more and more commonplace.
Remember, without antibiotics and vaccines, invading microbes gave us at least as much trouble as chronic inflammation gives us now. The biggest difference is that we’ve found ways to help our own immune system deal with signal #1, and use it to our own advantage. Logically, the next step is to find ways to help our immune system deal with signal #2. Indeed, that’s just what scientists are now doing. We are working on ways to tweak our immune response, including the response of our inflammasomes, for instance, so that we don’t end up with chronic inflammation after sensing signal #2. The goal? “Goldilocks” inflammation: we want to get that balance juuuuuuust right.
Until next week – reread Goldilocks! Scientists love her.
For more reading, this is a nice review paper!