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immunometabolism: in the micro-world
By | January 1, 2012
As you may know, I’m working on a cookbook. (It’s more than a cookbook.)
Because of it, I have been learning a lot about “metabolic syndrome” – what it truly is, how it works, what we can do about it. I’ve been talking to a lot of you about this stuff in the office. You may have heard me say, “Inflammation is the most basic function of our immune system, and whenever we have a system like inflammation, we have another system to tone it down, because you don’t want inflammation getting out of control.” Right? And I’m talking to you about it in the context of metabolism – how we break down and use the foods and other stuff we take into our bodies.
So in the course of reading about “immunometabolism,” I found this review article that intrigued me, not only because it uses fabulous words like “nonphlogistic recruitment” (remember phlogiston? the fire within?) and “efferocytosis” (Latin, “to take the dead cell to the grave”), but also because it describes the condition of inflammatory obesity in terms of (to me) high drama.
Imagine, if you will, the micro-world…
high drama
In the micro-world, a human being (or a chocolate labrador, or a lab rat, or any other complex creature) is not the master or director of conditions; they are, instead, the universe. Their activities (skipped breakfast, chased ducks at the lake, was injected with an experimental drug) are undectectable, except insofar as they provide the ambient temperature, the shifts in water acidity, the relative amounts of nutrients and pollutants, and are self-correcting to a greater or lesser extent, locally.
There are TONS of players in any ecosystem; I am only going to mention the ones that particularly interest me today, so please don’t scold me for neglecting to mention the key roles played by T-cells and nitric oxide and leptin, insulin and cortisol and ghrelin, etc.
The micro-world is full of players. The ones I’m thinking on today are certain cells.
fallopian tube: this way in
When you imagine “a cell,” you might imagine a bacterium or an ameoba – a blob with an eye, crawling around. That’s pretty close.
Cells are born as baby cells and are small and simple, and they develop skills and identities and finally have a characteristic look. A bone cell looks like one thing (spiky). A muscle cell looks like another thing (bamboo). A nerve cell looks like another thing (a tree). A skin cell looks like another thing (a brick). A fat cell looks like another thing (a water balloon).
A lot of cells congregate together and form rows and walls and layers, tissues – like muscle tissue, brain tissue, fatty tissue.
layers
Cells talk to each other the same way cats talk to each other – with a look, a smell, an attitude – sometimes a show of force, sometimes a strategic withdrawal, sometimes a sort of invisibility. Cats talk to each other through air and light. Cells talk to each other in the dark, under water.
Cells make chemicals that indicate things. I am trying to find a better vocabulary than we use in the hard sciences. For example, a ripe banana makes a chemical, due to being ripe. If a fruit-fly or a monkey or a bird notices this chemical, they might seek, find, and eat the banana. If they used a nose to detect the chemical, then we call the chemical a smell or a scent or a fragrance or an odor. What if they don’t have a nose? We might call it a chemoattractant – not a very poetic term. What if the smell is bad? If a nose is involved, it’s a stink. Without a nose, what is it? Something else.
l’eau de cytokine
Here’s another notion. In 1788, somebody imported rabbits to Australia, where they had no ‘natural enemies.’ The rabbits had a bazillion baby rabbits and basically ate up every green thing growing on the land, because nothing could stop them except running out of clover. They are making Australia a desert. But it’s not the rabbit’s intention to do so – they are just going on about their normal rabbit business. One could say that the rabbits are “sending a signal” that isn’t being received or responded to properly by the “environment.” Usually “the environment,” receiving the “signal,” would fix the situation (hawks and foxes and cats would eat the rabbits).
Similarly, something weird might happen to a cell, so that it just keeps growing, out of control. Weird cells have an effect on the environment. The “signals” they send may or may not be properly “received.” The immune system may or may not send its hawks and foxes and cats to wipe them out, or at least to keep them in check. The environment will either seek balance, or adjust to the new normal. As with the rabbits in Australia, we personally may or may not be pleased with the results.
like with kudzu
Unfortunately, in the science of the micro-world, we do not have a very good vocabulary to describe this. We say things like,
“Cells exchange signals to maintain their phenotypes and to optimize their functions. When a cell receives a signal, it sets off complex cascades that trigger and modulate the activities of numerous genes and proteins.”
Sheesh! I suppose it’s accurate, but it’s not evocative. It evokes nothing, except a stuffed shirt. These are living organisms, in functional ecosystems. Just because they’re teensy doesn’t mean their lives aren’t complex.
jelly jelly
I usually make cells sound like creatures, even though, like jellyfish, they have no central nervous systems. I imagine their “nervous system” – the patterns which enable them to get things done in a coordinated way – is more like a communications network (or a zeitgeist), than a specific individual goal-driven or teleological set of behaviors.
So imagine, if you will, this micro-world. Here is a fat cell – an “adipose” cell.
belly belly
Adipocytes look like water balloons. That’s not the prettiest picture. Here’s a nicer one:
As babies, they lived in the walls of the blood vessels that run through the fat tissue. When high amounts of nutrients ran through the blood vessels, the baby fat cells started growing up, and moved out into the adipose tissue – a forest of fat cells, all crowded together – next door.
As babies, they looked like regular cells, with one eye (a nucleus) and the usual internal organs, but as they started their normal job of absorbing and storing droplets of oil, they expanded bigger and bigger, so the eye and the internal organs got squished off to one side. This is why, as grownup cells, they look like water balloons.
You might wonder how we can take pictures of these cells, and why they are these various colors. Normally, they are so small that to our eyes, they are basically see-through. What we do is grab some (via blood test, biopsy, scraping, etc.), stain them with colors, and put them in the kind of environment they started out in. (If you looked at them in dry air, they’d be like collapsed balloons.)
a biggish blood vessel.
Why do adipose cells have this job?
Droplets of oil are fatty acids and triglycerides. They can be used as emergency fuel when there’s not a lot of blood sugar around, but they also can be toxic and harmful to most cells in general. All cells absorb fats, but adipose cells soak up more.
You don’t want a buildup of fatty acids, inside your blood vessels (atherosclerosis), your liver cells (steatohepatitis), your pancreas that is supposed to be making insulin (pancreatic steatosis).
That acid doesn’t belong there, and those cells have to work hard to detoxify it and get rid of it, taking energy away from what they normally should be doing. Sometimes they aren’t able to detoxify it, and the heart muscle, liver, and pancreas cells get sick and weak.
bluck
Luckily, there are adipose cells – starting as babies in the blood vessel walls, sensing excessive amounts of nutrients in the blood – that will soak up and store these acids, and keep them away from other cells.
Adipose cells, like all cells, need a supply of oxygen to stay alive. They are just single cells; they do not have a heart or blood vessels of their own. Oxygen, riding on red blood cells through the bloodstream, simply falls off the red blood cells and leaks through the blood vessel walls, into the adipose cells. However, as the adipose cells collect more and more oil, and get bigger and bigger, eventually it’s just too far for oxygen to travel, and a lot of cells that are far away from blood vessels become starved for oxygen, and start to die.
It’s like blood in the water: the sharks come out. When cells are dying, other cells start coming around to eat up the debris.
Sharks? Macrophages. From the Greek, “macro,” big, + “phagos,” glutton. They literally eat stuff – odds and ends of sugars and proteins, dead cells, etc. Here’s one, in a 30-second movie. It’s chasing a bacterium around, in and out amongst some red blood cells. (A neutrophil is like a macrophage for bacteria.)
Like sharks, macrophages travel from far away to gather in bunches – once again, not talking to one another through light or air, but communicating underwater and in the dark, through a smell, a change in temperature, a flavor, however you want to imagine the “chemical signals” they possess. Remember, like the ripe banana being eaten by the fruitfly, they don’t necessarily choose or intend to set in motion a chain of events – it’s just a natural outcome of their normal behaviors and life cycles.
mac.
How do they get to where the action is? They float around in the bloodstream until something attracts their attention, and then they wiggle out into the tissues – like diving off the freeway into the jungle. Another way of looking at it is, they float along until something grabs them, like someone in a flood getting yanked out by the leg.
If you ask me, this is tricky. You don’t want to be punching a hole in the side of the blood vessel, you don’t want the blood vessel seams to be loose and flimsy – they’re under blood pressure, and could spring a leak. But macrophages – like T-cells and other kinds of white blood cells – do squiggle out into the tissue, following whatever trail they are following. Here’s a 40-second reenactment.
Macrophages will behave in certain ways – and even look certain ways – depending on the environment around them. They have superpowers of being able to function in low-oxygen conditions. When they are attacking stuff, in an inflammatory way, spraying poisons around and eating up debris, we call them by the unromantic name “M-1.” Like attack elephants, they can be indiscriminate, and cause a lot of extra damage.
However, they relieve the pressure. The oxygen content starts to improve. If all goes well, the ecosystem starts to re-balance. The macs start to change in character and become “M-2.”
“Macrophages downregulate their proinflammatory activity and shift their function towards local resolution of inflammation and tissue repair.”
This really does mean making new tissue, new cells to replace the ruined ones, new blood vessels. Now the previously-rampaging elephants pitch in to rebuild walls, clear roads, and generally make things better than they were before.
Some will change up even further, and become “M-res” macs – “resolution” macrophages. These carry away the dead. When cells die, you don’t want them to just suddenly explode – for example, if they’re fat cells, they would spray fatty acids everywhere; if they are immune cells (like neutrophils), they’re full of bleach and peroxide and other other nasty bacteria-killing stuff. The “resolution macrophages” engulf these dead cells whole, and carry them away out of the area.
At any given time, tissues have a certain number of macs that hang around. Under healthy conditions, most of them are the friendly, helpful M-2s. But if things go haywire, you get a higher population of strong, savage, attacking M-1s. What if this happens without an obvious suspect, like a staph germ in your lung, a tapeworm in your belly, or a tumor in your gut? Then the attack just generally creates mayhem wherever it happens to occur. You get chronic inflammation, to a greater or lesser degree.
When we are looking at the micro-world to find out how inflammatory obesity occurs, we are looking at immunometabolism. Let’s review:
baby fat cells, with tiny droplets
Baby fat cells, in the walls of tiny blood vessels, are bathed in floods and floods of nutrients, because we eat too much (too much starch and sugar and fat and protein), for most of our lives. They gather together, they encourage one another, they coordinate activities to form fatty tissue, to store away the strong stuff – the overload, day-in-day-out, of acidic oil, one of the main results of your egg-and-pancake breakfast, your deluxe burrito lunch, the snickers snacks, the mac and cheese, etc.
They gather in bigger and bigger crowds – far from the blood vessels carrying oxygen. They fill up fuller and fuller with oil – they crush their own internal organs under the weight, trying to sequester all that oil.
Some die. Some spring leaks. Free fatty acids float around in the tissue. And it’s strong stuff.
“The response of the adipose vasculature and stroma to adipose expansion is often insufficient, leading to hypoxia and overcrowding… This perturbs adipocyte integrity and function and may lead to apoptosis and necrosis… resulting in the spill-over of free fatty acids into the circulation. Excess circulating free saturated fatty acids are harmful to the vasculature and also [build up] in numerous organs, including liver and muscle. Insulin resistance and lipotoxicity ensue.”
What do the macrophages see? Dying cells, toxic crud, low oxygen levels… could be a staph infection. Could be a tapeworm. Could be a tumor. They see red. And if they’re in stressed, wounded, sick adipose tissue, they see it everywhere they go.
clear lipid, red macs
“In lean, healthy mammals, macrophages account for approximately 10% of adipose tissue cellularity and are interspersed between adipocytes” – mostly M-2, build-and-repair macs.
“Obesity is accompanied by a robust influx [of] M1 macrophages… reaching 40% of adipose tissue cellularity. These staggering statistics exemplify the concept of an inflamed adipose tissue.”
Did you see those numbers? When the little village was small and efficient, one in ten citizens was a beat cop, helping folks out, jumping dead batteries for people.
When it became a crowded, polluted, crime-infested urban area, four in ten citizens was not just a cop, but an armed thug, jumping people for batteries.
Is that too much of a stretch? Try this instead:
When my belly fat was just a regular layer of warm insulation over the muscles, a few of the cells in there were build-and-repair macrophages, cleaning up any debris from micro-injuries and wear and tear.
However, when my belly fat became as big and heavy as three grocery bags full of food, almost half the cells were inflammatory macrophages… doing, ominously, what they do.
“The inflamed adipose tissue of obesity resembles an organ chronically infected by an intracellular organism, despite the absence of any pathogen.”
Your body – in the micro-world – is a universe of individual cells, coordinating their activities as appears appropriate given environmental conditions, and/or wreaking havoc for one reason or another.
Even if you could somehow command the actions of one of the individual players, it wouldn’t make any difference… you must instead seek to be influential over the whole situation.
How can you – your brain, your soul, your pure intention, and what you do – influence this ecology?
Further reading:
Lipotoxicity: http://diabetes.diabetesjournals.org/content/50/suppl_1/S118.full.pdf
Adipose hypoxia: http://diabetes.diabetesjournals.org/content/58/1/95.full.pdf
Inflamed fat: http://www.jci.org/articles/view/27280
Macrophage transformations: http://www.frontiersin.org/inflammation/10.3389/fimmu.2011.00049/full
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