Saturday, October 08, 2011

For The Man With a Macrophage, Everything is Inflammation

I was trying to explain to the kid how the immune system works in terms of superheros, ie leukocytes are like the Justice League, antibodies are like, uhm, sidekicks? Yeah well, doesn't really work. The whole point was to get him to understand that eating crap screws with the immune system, so stop asking for ice cream every day when we pass the shop. As you can guess, there's still a lot of work to do there.

Anyway, I came across these cool videos on YouTube trying to illustrate things, and it prompted me to read more about macrophages.

Here's some pathogens in the bloodstream glomming onto a white blood cell (lymphocyte? doesn't say what kind) then a pathogen getting glommed by antibodies, then eaten by a macrophage:


And here's a macrophage realizing there's a full-on alien invasion and sending out a distress signal in the form of  inflammatory (put out the Bat Signal) cytokines:


Best of all, here's a neutrophil chasing a bacterium with Benny Hill music:


I think it is pretty fascinating that macrophages not only eat pathogens (and debris), they repair muscle damage, including hormetic damage such as pumping iron. Macrophages repairing damage release anti-inflammatory cytokines.

To quote Robert McLeod, a much more knowledgeable person on this subject:
  • M1 macrophages are pro-inflammatory and fight infection.  They are the classical state for macrophages that you would find described in a textbook.  Primarily, they detect and fight foreign organisms (viruses, bacteria, and parasites).  They are characterized by the production of pro-inflammatory cytokines, chemicals which alert the other cell types of your immune system to react and destroy the invader (as well as adjacent 'self' cells). 
  • M2 macrophages are anti-inflammatory and repair tissue damage.  For example, when you exercise and your muscle tissue is damaged, it is M2 macrophages that infiltrate your muscle organs and affect the repairs [Tidball, 2010] after the initial M1 surge.  The characteristic cytokine of M2 macrophages is interleukin-10 (IL-10), which encourages other macrophages to enter the tissue and differentiate into M2 phenotype but also discourage the attention of cyto-toxic 'killer' cells from the lymphocyte family of the immune system.
If one believes that diseases of civilization (DOCs) are caused by chronic inflammation which is in turn caused by neolithic agents of disease (NADs), which I definitely do, then the role of macrophages and their cytokines becomes of vital interest.

Now I'm going to add in another element, this one's more controversial, more tentative but it's been gaining a lot of traction in the last few years, that DOCs are caused by chronic infection. Robert McLeod gave a good summary of this back in 2009, and Paul Jaminet is a firm believer in this. Assuming the chronic infection theory is true, who is supposed to be gobbling up these pathogens that are hiding out in our bodies for years on end? That's right, macrophages. Now we have muscle repair, chronic inflammation, chronic disease and reality television all tied up with macrophages and cytokines.

McLeod again:
The differentiation of macrophages, from M1 to M2, is not all that distinct and is generally though to represent the two extremes of a continuum.   My reading suggests macrophage populations can make the transition from one phenotype to the other, without die-offs.  This is probably a bad thing for chronic modern diseases, in that many of the diseases that are as a result of macrophage dysfunction occur when apoptosis (programmed cell death) is impeded.

One of the beneficial effects of eating a diet low in inflammatory factors (e.g. fructose, wheat, smoking) is that the overall levels of pro-inflammatory hormones, such as cortisol or interferon, are low so the transition from high M1 expression to high M2 expression can occur more rapidly. I strongly suspect this is why most people who transition to the paleo-diet are much better able to put on muscle mass. As the Tidball article indicates, chronic exercise is another no-no because it doesn't give enough time for the M2 macrophages to enter and affect repairs, so the muscle is always in an inflamed state.   
First of all, I've got the chronic exercise thing totally nailed. I'm a world-class not chronic exerciser.

The ability to transition and ratio of inflamatory/anti-inflamatory (M1/M2) is apparently quite important and is likely related to the amount of NADs we eat. Oh and guess where tons of M1 macrophages belching out inflammatory cytokines love to congregate? Yeah, in fat tissue. Especially belly fat of fat people. McLeod quoting a gated article by Olefsky and Glass:
The discovery that adipose tissue from obese mice and humans is infiltrated with increased numbers of macrophages provided a major mechanistic advance into understanding how obesity propagates inflammation (4, 5). Adipose tissue contains bone marrow–derived macrophages, and the content of these macrophages tracks with the degree of obesity (4, 5, 31, 32). In some reports, greater than 40% of the total adipose tissue cell content from obese rodents and humans can be composed of macrophages, compared with ~10% in lean counterparts (32).
Wow, more than 40% of fat tissue composed of macrophages screaming, "CODE RED!!!" That's a pretty stunning number. The obvious solution is to make a drug that reduces M1 macrophages to combine with the statins right? Then we'll have fixed things right and proper!

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