I read once more a great review of the CCL5/CCR5 axis. For the vast majority of us who are not Ohm, immunologists, etc, it remains a great review. It has a great review of the oft-mentioned downstream pathways inhibited by leronlimab.
https://www.sciencedirect.com/science/article...422100101X
https://www.sciencedirect.com/science/article...422100101X
Quote:Downstream pathway of CCL5/CCR5
It has been reported that the downstream pathway of CCL5/CCR5 including PI3K/AKT, NF-κB, HIF-
, RAS-ERK-MEK, JAK-STAT and TGF-β-smad pathways are associated with cell proliferation, angiogenesis, apoptosis, invasion, division, metastasis and inflammation.5,17, 18, 19, 20
CCL5/CCR5 axis could contribute to the activation of AKT and GSK-3β in PI3K/AKT pathway, thus regulating its downstream. Specifically, PI3K gets phosphorylated after CCL5 binding to CCR5, and contributes to the phosphorylation of the serine 473 of AKT. The AKT/PKB complex then phosphorylates GSK-3 to interrupt its activities. The expression of several downstream proteins is either activated or arrested (Fig. 1A).20 For example, the expression level of Bcl2 is upregulated to promote cell apoptosis;21
-catenin gets phosphorylated and then degraded; the level of Cyclin D, a crucial protein for the regulation of cell cycle, can be arrested by inactivated GSK-3.23 In the PI3K/AKT/mTOR pathway, CCL5/CCR5 phosphorylates 4E-BP1, which pushes mTOR-4E-BP1/S6K1-eIF4F pathway forwards. As soon as mTOR, a tyrosine kinase, receiving signaling from CCL5/CCR5-PI3K/AKT, it phosphorylates 4E-BP1, S6K1 and eIF4F gradually. After that, activated eIF4F disassociates 5′-untranslated region (UTR) and promotes mRNA translation. Moreover, CCL5/CCR5-mediated-PI3K/AKT phosphorylates Thr1462 of TSC-2, thereby prevent the formation of TSC-1/TSC-2 complex. This mediates the de-inhibition of Rheb, promoting the activation of mTOR and its downstream pathways (Fig. 1B). In reverse, mTOR can directly activate AKT pathway and send signals downstream.CCL5/CCR5 could also activate hypoxia inducible factor α (HIF-α) pathway by improving the stability and accumulation of HIF-1α. At a hypoxia situation, HIF-α initiates angiogenesis processes via a von Hippel Lindau protein (VHL) related ubiquitin degradation or HIF response element (HRE) (Fig. 2). CCL5/CCR5 phosphorylated p65 serine 536 can modulate signaling at both protein and mRNA levels through NK-κB pathway with a co-activator(Fig. 3). Up to date, it has been found that NF-κB pathway is associated with up-regulated expression level of Inhibitors of Apoptosis Proteins (IAPs), FLICE-like inhibitory proteins (FLIPs) and matrix metalloproteinase (MMP) proapoptotic protein as well as lower p53 level. CCL5/CCR5 can initiate RAS-ERK-MEK pathway by phosphorylating MEK and enhancing the kinase activity. For example, while downstream proteins like Msk1, RSK and Mnk1 are secreted for contributing to chromatin remodeling or protein synthesis, Ets, ELK-1 and SAP-1 are able to modify transcription. In addition, the activation can activate PI3K/AKT pathway to act synergistically. JAKs at adjacent receptors approach each other and get trans-phosphorylation after CCL5/CCR5 combination. Src homology 2 domain (SH2) of STAT and SOCS (suppressor of cytokine signaling) family enable receptor binding, which promotes gene transcription. As evinced by the T cell lymphoma seen in clinical patients' tissues, CCL5/CCR5 upregulate DNA methyltransferase 1 (DNMT1) expression level in malignant T cells. Additionally, tumor associate macrophage, especially M2 macrophage, release CCL5 to stimulate DNMT1 expression in ACG and HR cell lines in gastric cancer process.
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