I know that, in vitro, GM-CSF is used to polarize monocytes into "M1", before another stimulus, ex. LPS. I also know that chronic wounds tend to suffer from an abundance of M1 macrophages, and that they do not heal, in part, due to this problem.
HOWEVER, I am finding several studies showing that GM-CSF is actually beneficial in wound healing, especially chronic wounds. This doesn't make sense to me, as I would think the M2 phenotype would need to be promoted.
Does anyone have an explanation (or know of a paper) as to why this "M1 stimulus" promotes healing? Am I over-simpiflying the effects of GM-CSF on macrophages?
Please help clarify!
Dear Paulina,
The inflammatory response is not always bad. In fact we do need inflammation to alert our immune system.
M1 macrophages are know Pro-inflammatory cells (induce inflammation). In wound healing there is a need to recruit more macrophages (M1) to increase the inflammatory response and alert other immune cells to come and join the fight with microorganisms, this can be achieved through maturation of monocytes to M1 (to increase the inflammatory response) and thus increase the recruitment of other immune cells.
Very Best
Paulina,
I beleive that you are assuming that macrophages are the only cell type that respond to GMCSF, an do so universally by expressing the M1 phenotypic.
1. It may surprise you to learn that many epithelial cells also express receptors and respond to GMCSF.
How might these cells respond to GMCSF in vivo? Do you think this may contribute to wound healing?
And what about other species in the wound environment that might interact with GMCSF (i.e. extracellular binding species, e.g. vitronectin), directly or indirectly? Just because GMCSF is detectable does not imply that is bioavailable, nor that it is biofunctional, nor that macrophages are the only cell type capable of responding to GMSCF.
2. When we talk about M1 & M2 cells, do not presume that all cells in the population will be one or the other. When we talk about specific cell populations, do not presume that every cell in the population is identical. It is the nature of populations that individuals will express a gradient of measurable indicators (note: I do not use the term 'biomarker'; it is meaningless!). The term M1 or M2 is used loosely to indicate the 'majority' of cells within the entire population appear to express a phenotype consistent with M1, or M2.The ratio of these populations will never be 100%. And what's to say other phenotypes do not exist? The M1M2 transition is an analogue continuum, it is not simply M1 or M2 (a digital continuum).
The take home message? Nature is not black or white; on or off; i.e. digital.
Rather natural systems are an expression of statistical probability that Y is more likely than X. There is no such thing as absolute homogeneity. In contrast to the absolutes engineers speak of, biologists deal with 'shades of grey' – there are no absolutes in living things.
Yes, thank you David! As I read and researched further, I learned that many other wound cells respond to GM-CSF as well, and that macrophages produce a variety of "M1/M2" cytokines in response to it. Thank you for the explanation!
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