Quote: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?
Collagen deposition does not induce inflammatory factors in fact collagen has anti-inflammatory factors. Inflammatory chemokines trigger STAT3 in an attempt to repair the damage being caused to the body. The problem with NASH is that it's not a temporary inflammatory condition. Chronic conditions can lead to an over-inflammatory response and an over-response to healing.
Quote: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?
M2 macrophage proliferation will mean continued extracellular matrix and collagen deposition so M2 doesn't accomplish both. Matrix metalloproteinase-2 (MMP-2) is most responsible for ECM/collagen fibrotic degradation. MMP-2 is preferentially expressed in M1 macrophages. Tissue inhibitors of metalloproteinases (TIMPs) downregulate MMPs. CCR5 downregulates both MMPs and TIMPs which should bring about some balance.
Quote: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?
I am assuming you are talking about the leronlimab phase 2 NASH study. You have it ass-backwards. Recknor never says fibrogenesis upregulates CCL3. CCL3 is one of the inflammatory chemokines that drive fibrogenesis. The high level of CCL3 is because of the underlying condition of liver fat.
Quote:These chemokines* act as a beacon to attract other cells in the area. The difference is really big because we thought we just worked on CCR5, but we are also working on CCL2, 3, 11 and 18*. In NASH studies, we can see correlation b/w* CCL3 which is Macrophage Inflammatory Protein Alpha 1 levels and they increase in severity of NASH on biopsies. So patients in full blown NASH, show highest levels of CCL3*
Quote:So then, you're saying that by adding LRM, even to the point of 100% RO, this should flip all the Macrophages to M1.
I never said that, there are other factors that effect M1 polarization. STAT3 is just a large one.
Quote: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.
You seem to be confused. The reduction is the differential between baseline and after treatment with leronlimab. As I pointed out leronlimab would decrease inflammatory factors.
As for the rest of it, I'm tired of reading gobbledygook.
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