Quote:Inflammatory chemokines are induced by the CCR5 ligands and activate STAT3 which flips macrophages to M2. The inflammatory stage (M1 macrophages) is what causes the M2 macrophages to be needed for repair. High levels of M1 macrophages causing excessive apoptosis, bad. High levels of M2 macrophages causing excess collagen deposition and extracellular matrix, even worse.
So if Inflammation is what flips Macrophages from M1 to M2, and if the M2 stage of excess collagen deposition is so much more so Inflammatory, where do the Macrophages go from there?
I guess you are in agreement that the laying down of fibrosis, that is both fibrogenesis as well as the resorption of fiber are both metabolized by M2 Macrophages. Am I right in thinking that any kind of metabolism of fiber, be it fibrogenesis or fiber resorption, are both accomplished by M2 macrophages?
But according to the study, Fibrogenesis is what leads to an increase in CCL3 and since by the definition of CCL3, an upregulation of CCL3 would happen in M1, then whenever CCL3 is elevated, the Macrophages would be operating in M1, even though Fibrogenesis happens in M2 according to the study. Could the study be wrong?
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Here's where the magic happens. Leronlimab knocks down the inflammatory chemokines disrupting the PI3K/AKT/mTORc/ STAT3 pathway and reverting macrophages to M1. The M1 macrophages would ordinarily induce a high inflammatory state, cell death and an even higher inflammatory state. But CCR5 blockade by leronlimab keeps that high inflammatory state from happening.
So leronlimab reduces the inflammation and reduces the M2 macrophages from creating fibrosis.
So then, you're saying that by adding LRM, even to the point of 100% RO, this should flip all the Macrophages to M1. Now, because it is Leronlimab and not RANTES or another chemokine, inflammation should be held at a minimum.
If we look at the Heat Map and you look at the horizontal lines of both INF gamma as well as CCL3, (Macrophage Inflammatory Protein 1 Alpha MIP1 alpha), you will see that these 2 look identical and when elevated, would point towards being in M1. Also, if you look at IL-4 which would be increased in M2, it almost looks like the opposite of INF gamma and CCL3.
Therefore, the increased presence of both INF gamma and CCL3 along with the reduced presence of IL-4 would point to being in M1 mode. And the opposite is true, the reduced presence of both INF gamma and CCL3 coinciding with the increased presence of IL-4 would point to being in M2 mode.
For the most part this correlates with the Heat Map, except for (2) instances, where (1) 700HM IL-4 is increased where it should be black or green/decreased. Why was IL4 increased in HM where the dosage was better matched to the receptor quantity? Was there a greater tendency to enter M2 mode and metabolize fiber even despite the fact that both interferon gamma and CCL3 were both screaming that the Macrophages were in M1 mode, and this happened only when LRM was properly dosed?
And (2), there was also another discrepancy in the slight reduction in IL4 in the 350mg > 950 ms cT1 group. This should have been black or red like the other (2) 350 rectangles if it were to correlate. Why was it reduced/green? Why was IL4 reduced when only 350mg was given to patients who had severe fibrosis to begin with? With all this fibrosis, there was less of a tendency to maintain M2 mode? Maybe cause the loss in cT1 was -68.86ms p=0.009 and that it was that massive loss of fibrous tissue which led to the reduced IL-4, the reduced push or need to maintain M2 mode, despite the fact that Interferon Gamma and CCL3 were both saying the system is in M2. Maybe because the 350mg dose was so effective at that level that it brought cT1 so low, that there was less of a need to remain in the M2 mode.
I don't agree with the Magic which you describe. Leronlimab does not solely revert the Macrophages to M1, but rather it allows the Macrophages to operate where they should operate to reduce the disease and increase health. Leronlimab allows for the proper communication between the immune cells so that the decisions of the T cells and the T regs can be properly made without a confounding presence of RANTES around. Also, M2 is not an inflammatory state.
This is ANTI-INFLAMMATORY.Quote:This early IL-4 production rapidly converts resident macrophages into a population of cells that are programmed to promote wound healing;
Macrophages treated in vitro with IL-4 and/or IL-13 fail to present antigen to T cells, produce minimal amounts of pro-inflammatory cytokines and are less efficient than classically activated macrophages at producing toxic oxygen and nitrogen radicals, and at killing intra cellular pathogens. However, these cells secrete components of the extracellular matrix and therefore their primary function seems to be related to wound healing. These macrophages can also exert indirect regulatory effects on the immune response because the polyamines they produce can influence the production of cytokines and suppress the clonal expansion of neighbouring lymphocytes
When M2 is activated in a Macrophage, it is impossible for that Macrophage to perform in the M1 mode and vic versa. The Macrophage does 1 of 3 things only. It M1) kills/destroys, it M2) heals or it lies dormant in quiescence as Macrophage Regulator. When it kills and destroys, that is inflammatory. The healing part leans towards calming down while it rebuilds vasculature and lays down collagen and fibrotic tissue which leads to scarring. This is not inflammatory, The laying down of fiber is a means to reduce inflammation and swelling, otherwise, you would have bleeding gaps where the necrotic hepatocytes died with open wounds. The act of fibrosis is that of a healing role, but we have to undo that anyway and that is why I think the M2 mode is that of 2 functions, fibrogenesis and fibrous resorption. It is a give and take of the existing fibrous tissue. Add more and/or take away from.
With the proper dosing of leronlimab, the cytokines function appropriately to allow the appropriate time period for the Macrophages to remain in M2 mode to eradicate and metabolize the fiber if it exists and the time to remain in M1 to address the sick hepatocytes if they call, which subsequently addresses the steatosis and tends to restore the liver back to health.
Leronlimab doesn't have any direct anti-inflammatory effects by increased RO, it induces reduced inflammation by effecting a healing response within the body, by permitting and allowing the proper cytokine signaling to get the job done without the confounding influence of RANTES disrupting the correct mechanism of action.
