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Microbes & Immunity RANTES/CCL5 and ezrin peptide RepG3 for long COVID

various HIV antigen-specific CD8 T-cell clones and HIV- morphology; the cells push out a probe at the front of the
+
specific CTL activity. 66 cell and develop a projection at the rear of the cell termed
the “uropod,” where inter-cellular adhesion molecules
4.7. High concentration RANTES/CCL5 is a non- concentrate. During the journey of lymphocytes,
specific activator of T-cells monocytes, and macrophages toward a focus of
In contrast to the regulated immune amplification by inflammation, they also exit blood vessels in a process
physiological nanomolar doses of RANTES/CCL5, ultra- called “extravasation.”
high micromolar doses of RANTES/CCL5 non-specifically RANTES/CCL5 stimulation also changes the spatial
activate T-cells. This ultra-high-dose activation effect of organization of protein complexes at the cell membrane,
RANTES/CCL5 on T-cells resembles mitogenic activation acting on ezrin-actin multi-protein complexes to drive
by phytohemagglutinin (PHA) or anti-CD3 antibodies. 67 directional migration. In migrating leukocytes, RANTES/
Self-aggregation of RANTES/CCL5 occurs at ultra-high CCL5 induces clusters of chemokine receptors, such as
culture concentrations, for example, 5 µM RANTES/CCL5 CCR5 and CCR1, at the leading edge of migrating cells
in vitro, which is equivalent to about 39,000 ng/mL (at least while concentrating adhesion molecules, such as ICAM-1,
4000 times greater than physiological concentration). The ICAM-3, CD43, and CD44, on the trailing uropod. 68
ultra-high dose also results in RANTES/CCL5 binding to
cell surface glycosaminoglycans, creating RANTES/CCL5 4.9. RANTES/CCL5 activation of astrocytes in the
deposits on the surface of T-cells, which can be visualized brain
by surface staining and flow cytometry. In cell cultures of astrocytes of the brain, 100 ng/ml

The effects of these ultra-high doses of RANTES/ RANTES/CCL5 induces phosphorylation of MEK, ERK1,
CCL5 on T-cells in vitro include intracellular calcium and ERK2 within 5 min, which peaks after 40 min and then
mobilization in a few seconds, rapid ezrin-actin cytoskeletal declines over the following 2 h. Activated MEK results in
re-organization, including ICAM-1 expression within the phosphorylation of ERK1/2 and p90 ribosomal S6
10 min, changes in cell-shape, and cell-clustering. There is kinases (RSK) and the expression of anti-inflammatory
also cell-surface expression of the early activation marker IL-10.
CD69 and the induction of tyrosine kinase activity of the Between 5 and 20 min after RANTES/CCL5 treatment,
zeta-associated protein 70 (ZAP-70), which is normally high levels of phosphorylated RSK concentrate within
regulated by an antigen-activated T-cell receptor. In the nucleus, resulting in the phosphorylation of the
addition, CD25 (IL-2 Receptor), HLA-DR (MHC Class 2 transcription factor CREB at Ser-133. The activation of
antigen-presenting protein), CD11b, and CD11c (integrin gene expression is initiated by phospho-CREB binding
adhesion molecules) appear on the cell membrane, and to the CRE element in the upstream gene promoters.
MIP-1β and IFN-γ are secreted into the intercellular The activation of CREB is essential for RANTES/CCL5-
medium. This non-specific activation by ultra-high mediated induction of chemokine transcription and
concentrations of RANTES/CCL5 is not confined to increased RANTES/CCL5 secretion.
T-cells; it also occurs in monocytes and neutrophils. In the nucleus, activated CREB competitively

4.8. RANTES/CCL5 induces migration of inhibits transcription factor NF-κB transcription of
lymphocytes, NK-cells, and monocytes proinflammatory cytokines by acquiring most of the
available transcription co-factors “CREB-binding protein”
Leukocyte migration is involved in the induction of (CBP) and p300, which are also required for NF-κB
immune responses, interactions between APCs and transcription. RANTES/CCL5 does not activate the p38
T-cells, T-cell help to B-cells, CTL targeting and killing, MAPK > NF-κB mediated proinflammatory cytokine
and NK cell targeting and killing. Cell culture experiments expression pathways. 69
have demonstrated that RANTES/CCL5 induces cells
to become mobile and is a potent chemoattractant for 4.10. RANTES/CCL5 upregulates IL-10 expression
memory T-cells, monocytes and macrophages, NK cells, The injection of RANTES/CCL5 into rats increases the
eosinophils, dendritic cells, and basophils. Nanomolar anti-inflammatory cytokine IL-10 and decreases blood
concentrations of RANTES/CCL5 in vitro engage CCR5 pressure. The effect is dependent on the dose of RANTES/
receptors to induce a G-protein, PKC, ezrin, and p38 CCL5; doses of RANTES/CCL5 from 10 ng/mL to
MAPK-dependent signal that triggers cell migration. 100 ng/mL gradually increase IL-10 mRNA expression
When stimulated to move and migrate, lymphocytes up to a plateau that occurs from 100 ng/mL to 400 ng/mL.
adopt a polarized phenotype resembling ameboid In spontaneously hypertensive rats, IL-10 downregulates

Volume 1 Issue 1 (2024) 11 doi: 10.36922/mi.2474