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).