Flipping Macrophages.
Arguably the most influential factor controlling Health. Why?
Macrophages are the Big Guns when it comes to the Immune System. And Your Immune System governs Inflammatory Pathways.
Ever heard of the line “Inflammation is the root of all Disease?”
Well, flipping Macrophages is the Antidote.
The idea of giving the everyday citizen the power to flip Macrophages with food and thus radically improve their level of Health was first publicly introduced by Joel Greene in his book The Immunity Code. In his book, Joel eloquently unravels the mechanisms that support flipping Macrophages metabolically and dives deep into drivers like the Gut Lining, Cellular Oxygenation, Commensal Bacteria, Meal Timing and Circadian Cycles.
The tissue of interest In the Immunity Code is Fat or Adipose Mass. Better known as the Stromal-Vascular Fraction. However, the principle of flipping Macrophages for Health carries over to multiple tissues, including Fascia.
In this pressurized and power-packing article I’m dispatching the goods and dispatching them fast. You’re going to learn What Macrophage Flipping is, Why it’s Important, A Couple of classic Modern Day examples of Macrophage Flipping gone sour, and how You can flip Macrophages not just metabolically, but mechanically as well.
WHAT IS MACROPHAGE FLIPPING?
To put it simply Macrophage Flipping is basically transforming an Immune Cell from one Mode to another.
In one Mode Macrophages will behave a certain way and in another mode they’ll behave completely differently.
Same Body, Different Behavior, and therefore Different Function.
Kind of like turning Minions to Zombies.
Each Mode is called a “Phenotype”.
What comes next is an oversimplification, but it’s also easy to digest and very useful.
In general Macrophages have a PRO-Inflammatory Phenotype and an ANTI-Inflammatory Phenotype. The Pro-Inflammatory supports Inflammation. When expressing this Phenotype, or acting in this “Mode”, Macrophages pump out free Radicals, cause damage & destroy invaders and recruit more pro-inflammatory Macrophages. The anti-inflammatory phenotype is the opposite. It expresses molecules that support cellular repair, stitches up & builds tissue and stimulates apoptosis (cell-death) of pro-inflammatory Macrophages.
Pro-Inflammatory are called M1 → Because they are the 1st Macrophages on the scene.
Anti-Inflammatory are called M2 → Because they are the 2nd Macrophages to arrive.
When M1’s move towards becoming M2 or M2’s move towards becoming M1 this is called “Polarization”.
Polarizing Macrophages is also called “Flipping.”
In order to polarize, or flip, Macrophages from one Phenotype to the next they require a signal.
This is how we can steer Immune Cell Populations in Our Bodies.
By providing signals.
Bada-bing, Bada-Boom, You are now a Scientist.
Biobabble and all.
Next time Your Friends ask You why Your icing Your steamed Potatoes You can tell them
“I’m polarizing M1 Macrophages towards the M2 Phenotype via metabolic signaling.”
Yep.
You My Friend, are officially the Coolest Person in the room..
WHY IS FLIPPING MACROPHAGES IMPORTANT?
Picture this.
Your Body is a sea of Cells. All mashed together to make 1 congruent, co-evolving community called a Human Being.
Within this Community exist departments, like Surveillance (Eyes), Air Filtration (Nose), Storage (Fat), Planning (Brain), Design (Fascia), Labor (Muscles), Energy Exchange (Liver) etc. Each of these departments are a tissue type within Your Body.
Each department is overseen by a Supervising Leader that is watching the big picture while also simultaneously accommodating for all the small obstacles that happen day-to-day. If something catastrophic happens and the entire department runs into a problem the Supervisor changes roles, hits the deck and starts organizing an effective response to return the department back to balance.
So if Larry opted to use the extension cable with the frayed end he found in the old coffee cupboard to plug in the 3-D Printer and an electrical fire starts, it only takes a handful of baking soda instead of the entire NY Fire Department to save the Day. (That’s for You David.)
This Supervisor is Your Macrophages.
And the act of observing is called Immune Surveillance.
When they act on an imbalance it’s called an Immune Response.
A handful of Macrophages has the power to direct an entire population of tissue Cells. To a degree tissue cells will even mimic the activity of an Immune Cell (Macrophage) and adopt their metabolic signature. This is how Macrophages adjust tissue cell activity.
To get to the meat of the matter, Immune Cells regulate tissue function at the uppermost level.
When Macrophage populations are balanced within a tissue, tissue function is healthy and Our Tissue operates at Homeostasis. Everything auto-adjusts and self-organizes to a greater degree of complexity and stability.
When Macrophage populations are imbalanced we see a dysregulated Immune response and we get Inflammatory problems & disease. Breaking away from self-organization and into erratic behavior and overemphasized demands that lose the intricacy of an expanded and interconnected web of relationships.
The Goal is a balanced Immune Population.
A balanced Immune population has a balanced distribution of M1 and M2 Macrophages. The ability to polarize or flip Your Macrophages from one phenotype to the other during times of imbalance allows You to steer Your Tissue Health.
Or as Joel puts it:
“The greatest degree of control will come from control of the controlling mechanisms.”
Pretty Wild right?
Absolutely.
MACROPHAGE FLIPPING GONE SOUR
Okay now that You are a next-level genius in understanding an immunecentric approach we are going to burn through some Modern Day Classic Examples, fast and furious style.
Here we go.
PTSD: Macrophages in the Brain are called Microglial Cells. Microglia are non-excitatory (electrical) cells in Your Nervous System. In PTSD, Microglia flip to the M1 phenotype and release pro-inflammatory cytokines like IL-6, IL-1a, TNFa and IFN-y. This recruits more M1’s and leads to severe behavioral disruption that actuates an anxiety response that self-perpetuates a loop between psychological stress and immune activation. This loop drives PTSD.
Obesity: LPS in the serum activates an inflammatory response in fat cells. Excessive M1’s induce Insulin resistance and shift metabolism in Fat tissue while perpetuating the inflammatory response and driving up fat storage. Progenitor adipocytes (Baby Fat Cells), become M1’s instead of Fat Cells and make the problem worse.
Muscle Fibrosis: Excessive M2 macrophages in muscle tissue creates an excessive deposition of collagen fibers replacing damaged muscle cells from exercise with fibers that build the ECM. This drives Muscle Fibrosis and loss of muscular function.
Fatty Liver: Kupffer Cells is the name given to Macrophages in Your Liver. An acute polarization towards M1 phenotype in kupffer cells leads to a prevention of fat-burning in the liver, an increase in fat accumulation and Insulin resistance in liver cells and increased fibrosis by turning liver cells into fibroblasts. All these responses are co-ordinated by pro-inflammatory cytokines.
We could go on with this list but I think You're getting the picture.
If You want to steer Your Health, steering immunity is currently Your best bet.
And you're about to learn how to do it.
MECHANICAL MACROPHAGE FLIPPING
If You haven’t picked up Joel greene’s book the Immunity Code yet I highly recommend it. It gives Yo a very simple, step-by-step, practical handbook that You can use t instantly begin shifting immune populations in key tissues in the body like Your Gut Lining, Your Liver and Your Fat.
A large part of the Immunecentric concept is built on Immunometabolism.
Immune - Metabolism.
Wait.
Immmun-O-metabolism.
Way catchier.
We Scientists do occasionally pride ourselves on our ever so clever and creative nomenclature.
Just in case this concept is still a little tough to chew, immunometabilism is essentially steering Macrophages phenotype based on what You feed them.
You are what they eat.
This of course, is one very powerful avenue.
But here we are going to equip You with the skill to flip Macrophages mechanically.
Instead of shifting metabolism or using food to flip Macrophages we can leverage mechanics or use structure to for the same thing.
Remember in order to polarize Macrophages require a signal. This signal can be a biochemical one but it can also be a mechanical cue that arises from the Tissue or the Extracellular Matrix (Flexible Fiberglass-like structure that every cell sits in). As Mechanical cues vibrate, tug, pull, squeeze or stretch, evolutionarily conserved pathways in Immune Cells and transform into a biochemical signal internally (inside the cell) to alter activity.
This is called Mechanotransduction.
Your Immune Cells can then respond in kind, playing part in the vibrational, pressure-based shear stress and fluid dynamics that form the mainline of communication in the mechanical micro-environment of Your cells.
Depending on which genes get activated or inactivated dictates which phenotype a Macrophage will present as.
In short:
Mechanical Stimuli → Change Shape of Macrophages → Changes Macrophage Phenotype
When a Macrophage is elongated like an oval it adopts an M2 Phenotype.
A smaller, compressed and circular cellular shape will yield an M1 Phenotype.
This is thanks to some very specific fibers in the cytoskeleton of a cell called F-Actin.
Think of F-Actin as Fast-Action.
When mechanical cues vibrate down the pipeline F-Actin quickly jumps into action changing the shape of the cell. When F-actin is loose and evenly dispersed it hangs out around the periphery of the cell, skimming along the outside edges and letting the macrophage stretch into an oval. When F-actin is stiffened it moves from the outside → in; clustering around the nucleus and keeping everything held tight and round.
But what kind of mechanical stimuli cause these F-Actin fibers to reorganize to create M1’s?
Stiffness.
Research has demonstrated that stiff fibers drive M1 polarization. What’s more is when nearby stretched by nearby cells to promote elongation M1’s will flip to become M2’s.
It seems to be that increase in Mechanical Tensioning increase M1 Macrophages.
And tight, round M1 Macrophages facilitate adhesion, attachment, proliferation, spreading and recruitment. Which, among other things, sounds an awful lot like cancer qualities, which funny enough also tend to show up when the ECM gets stiff.
Something to keep an eye on.
And perhaps get Your fingers into. (Butter up those tissues if You catch My connotation).
SUMMARY
Now that You’ve learned what flipping Macrophages is, why its a gamechanger to Your Health, and that changes in Cell Geometry is enough of a signal to polarize macrophages in whatever direction You choose maybe asking Your partner for an post-dinner massage might sound a little more convincing.
After all, it’s for Your Health.
…
Then again, that lacrosse Ball over there also looks a little lonely.
