Prior to this post, you said:

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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.

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.

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now you say:

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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.

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this is what makes it very difficult and I wish to continue such discussions for the good of all.

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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.

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Why would you assume that? In this same thread, you gave me a study named CCR1 and CCR5 Promote Hepatic Fibrosis in Mice. This is the study I was referring to.


Let's carry on...