A tissue macrophage will continuously adjust its expression of surface receptor proteins and secreted products in response to local stimuli, in a manner so similar to the T lymphocytes of the adaptive immune branch that the “Th1 vs. Th2” nomenclature has been adopted to classify macrophage activation as “M1 vs. M2.” “M1” activation describes a macrophage performing “classical” anti-microbial functions, while “M2” activation encompasses the “alternative,” quite literally, everything else— from helminth defense, to tissue repair in the wake of an oxidative burst, to feed-back regulation of the immune system.
M1 is to macrophages as Th1 is to lymphocytes; among other cytokines, Th1 cells can produce high levels of IFN-γ, an extremely potent macrophage chemoattractant, and also one of the most potent endogenous M1 macrophage activation stimuli. LPS (endotoxin) from bacteria can also stimulate M1 macrophages through TLR-4, and it is the most well described exogenous M1 stimuli. A macrophage so stimulated will produce high levels of TNF-α, IL-6 and IL-12, which have a variety of effects on stromal tissue cells. In addition to cytokine production, M1 activation stimulates iNOS (inducible nitric oxide synthetase)activity and phagocytosis, i.e. macrophages become better at consuming and destroying bacteria.
Similar to the M1 story, M2 is to macrophages as Th2 is to lymphocytes; Th2 cells can produce high levels of IL-4. IL-4 greatly stimulates the expression of mannose receptor, which is an opsonin (antibody)-independent cell surface particle receptor (or pattern-recognition receptor) and is widely accepted as the canonical marker for M2 macrophages. M2 activation also results in increased CD36 expression, which binds to oxidized low density lipoproteins, thrombospondin, and several other molecules. The increased levels of these scavenger receptor proteins on M2 macrophages is consistent with the need to clean out debris in order to successfully resolve, or end, an inflammatory response. Another role for the M2 activated macrophage is to react against invasion by helminth worms or other parasites. Accordingly, IL-4 stimulates the increased expression of acidic mammalian chitinase (AMCase), our only enzyme which can hydrolyze the shells of worm eggs into digestible and MHC Class II-presentable proteins.
This post was written for us by Jason Fritz, a PhD candidate in the School of Pharmacy, who took IMMU 7630 2 years ago and is the macrophage king!
M1 is to macrophages as Th1 is to lymphocytes; among other cytokines, Th1 cells can produce high levels of IFN-γ, an extremely potent macrophage chemoattractant, and also one of the most potent endogenous M1 macrophage activation stimuli. LPS (endotoxin) from bacteria can also stimulate M1 macrophages through TLR-4, and it is the most well described exogenous M1 stimuli. A macrophage so stimulated will produce high levels of TNF-α, IL-6 and IL-12, which have a variety of effects on stromal tissue cells. In addition to cytokine production, M1 activation stimulates iNOS (inducible nitric oxide synthetase)activity and phagocytosis, i.e. macrophages become better at consuming and destroying bacteria.
Similar to the M1 story, M2 is to macrophages as Th2 is to lymphocytes; Th2 cells can produce high levels of IL-4. IL-4 greatly stimulates the expression of mannose receptor, which is an opsonin (antibody)-independent cell surface particle receptor (or pattern-recognition receptor) and is widely accepted as the canonical marker for M2 macrophages. M2 activation also results in increased CD36 expression, which binds to oxidized low density lipoproteins, thrombospondin, and several other molecules. The increased levels of these scavenger receptor proteins on M2 macrophages is consistent with the need to clean out debris in order to successfully resolve, or end, an inflammatory response. Another role for the M2 activated macrophage is to react against invasion by helminth worms or other parasites. Accordingly, IL-4 stimulates the increased expression of acidic mammalian chitinase (AMCase), our only enzyme which can hydrolyze the shells of worm eggs into digestible and MHC Class II-presentable proteins.
This is a thorough introduction to M1 and M2 macrophages. However, I do have one issue with this article: M1, M2, Th1, LPS, TNF-α, etc; the letters become alphabet soup in my brain. So here’s what helped me distinguish between M1 and M2 macrophages. Polarity.
ReplyDeleteThese macrophages and lymphocytes are interacting and arranging themselves to produce TNF-α and interleukin responses from a variety of stimulus, and with 35 known interleukins, it can be difficult to predict why M2 is the designated macrophage for IL-4.
Here’s what I know- M2 is characterized by its role for metabolizing arginine and polyamides (among other things), so M2 is in charge of the positively charged molecules. I think that elaborating on this characteristic would have helped students understand the behavior of M1 and M2 macrophages a little better (just don’t ask me to do it, I’m out of information).
-The Wizard
On a completely different note, we were discussing the evils of unsupported supplements aimed at general symptoms. An article or Dear Abby popularizes an ailment and suddenly everyone is looking for the miracle cure. Wobenzyme was the example used. Looking into the supplement, I found that it is a combination of trypsin, bromelain and rutin. The proteolytic enzymes are meant to break down immune complexes that are precipitating out of the blood. There have been many studies performed including several that were double blind supporting signicant improvement and pain relief. One such study performed on men with chronic prostatitis showed the enzymes decreased pain as well as the level of protien and blood cells in the urine. The double blind study tested the enzyme against a placebo on a group of eighty men. This among other studies can be seen at: http://www.systemicenzymesupport.org/references/mu-694422.html
ReplyDeleteI just thought it was interesting that there is a lot of work going into "natural" remedies as well. From my untrained eye, the support looks pretty solid.
This is an instructive example of how the immune system is all about the yin and yang and moreover how our rugged classification of physiologic systems is more continuous than we often think. We commonly discuss how a Th1 vs. a Th2 response promotes different arms of the immune system (i.e., humoral or cell mediated) however the innate immune system was often though to be much too boring to be capable of anything interesting much less drive the adaptive response toward a specific end. Immunologic life is not without surprises and one of the oldest defense mechanisms plays a role in the more evolved adaptive system (which makes sense because the adaptive evolved around the innate). Perhaps the innate and adaptive are more intimate that we thought. According to Ricardo Et. Al. activation of M1 macrophages by a classical immune pathways is characterized by the production of IL-12 and IL-23, both of which strongly influences the outcome of the Th1, Th17, and CD4+ T cell response. It seems M2 macrophages are designed to fly under the Th2 response radar such that they can perform their jobs without being suppressed by Th2 cytokines and preform cleanup, tissue repair, and tissue proliferation. The M2 is a non-inflammatory macrophage. One further note: “polarization of macrophages” is more of an abstraction than a literal definition. M1 and M2 work under pro and anti-inflammatory environments respectively and polarization refers to the opposite functions probably not electrochemical charge.
ReplyDeleteRandy
Citation:
Macrophage diversity in renal injury and repair
Sharon D. Ricardo, Harry van Goor, Allison A. EddyJ. Clin. Invest. 2008; 118(11):3522
The post provides a good summary of the activation, but it seems that with most biological systems there exists a feedback mechanism to keep the activation localized (other than the diffusion rates of cytokines and chemokines). Does such a feedback mechanism exist (I apologise in advance if the answer is rather obvious)? Is it possible that the body may have two different localized responses to the same pathogen at once, in different tissues?
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