CCL21/CCR7 chemokine axis participates in the pathological
process of RA through regulating the PI3K signaling pathway
Angiogenesis is one of the main pathological features of RA, which
depends on the activation, migration and proliferation of endothelial
cells. Accordingly, inhibition of angiogenesis may provide a new
therapeutic approach for RA (MacDonald et al., 2018). Studies have found
that CCL21 and CCR7 were co-expressed on the endothelial cells of
synovial tissue. CCL21 can induce fibroblasts, macrophages and synovial
lining cells to produce pro-angiogenic factors in RA. Altogether, the
expression of CCL21 and CCR7 in RA blood vessels was linearly
correlated, suggesting that the CCCL21/CCR7 chemokine axis plays a vital
role in RA angiogenesis. Some studies have also shown that the
combination of CCL21 and CCR7 can induce HMVECs migration in the joints
of RA patients, but CCL19 has no effect on HMVECs migration. It may be
that CCL21 and CCL19 mediate different signal pathways (Hayashi et al.,
2009).
CCL21 was found to promote neovascularization at detectable
concentrations in RA joints. However, CCL21 promotes angiogenesis by
recruiting the accumulation of endothelial cells and endothelial
progenitor cells in RA synovial fluid and tissues. Further studies have
revealed that the binding of CCL21 to CCR7 regulates HMVEC migration and
angiogenesis by mediating the
activation of PI3K pathway. In vitro studies found that ERK, AKT1 and
PI3K were the first to be phosphorylated by CCL21 in HMVEC treated with
CCL21 for different durations, while JNK was activated last. However,
blocking the ERK and JNK pathways had no effect on the chemotaxis of
CCL21-induced HMVEC. Blocking the PI3K and AKT1 pathways can reduce the
chemotaxis of CCL21 (Jiang et al., 2008,
Van et al., 2020). Blocking PI3K
pathway can also reduce CCL21-mediated angiogenesis by 35-40%, while
blocking ERK and JNK pathways had no effect on angiogenesis. These
results indicate that CCL21 may induce HMVEC chemotaxis through
mediating PI3K and AKT1 pathways, and blocking PI3K pathway can reduce
the regulatory effect of CCL21 on HMVEC chemotaxis and angiogenesis. In
conclusion, blocking PI3K pathway can inhibit endothelial cells
migration and angiogenesis induced by the CCCL21/CCR7 chemokine axis in
RA. These findings suggest that inhibition of angiogenesis may provide a
new idea for the treatment of RA, and CCL21/CCR7 chemokine axis may also
be a new target for the treatment of RA (Cuesta-Mateos et al., 2010,
Calabresi et al., 2018)(Figure 4).