CCL21/CCR7 chemokine axis regulates the pathological process of autoimmune diseases
CCL21/CCR7 chemokine axis and RA
The pathogenesis of RA is related to the abnormal activation of T and B cells. Activated CD4+ T cells differentiate into special effector cells, which plays a essential role in specific immune responses. A large number of activated CD4+ T cells infiltrate the synovial tissues and secrete inflammatory cytokines, causing synovial inflammation in RA. The pathological manifestations of RA are synovitis, vasculitis and pannus formation (Zhao et al., 2019, Klammt et al., 2015). Chemokines are one of the important factors of lymphocyte infiltration in the synovial tissue of RA patients. In the pathogenesis of RA, chemokines regulate the selective recruitment of lymphocytes to the site of inflammation. The synergistic effect of chemokines and their receptors with adhesion molecules determines the invasion and proliferation ability of immune cells (Aldahlawi et al., 2015).
Genome-wide association studies (GWAS) study showed that CCL21 is a susceptibility gene for RA and has a variety of genetic polymorphisms related to RA. Studies have shown that CCR7 is highly expressed in DCs in animal models of collagen-induced arthritis (CIA), nevertheless, administration of CCR7 monoclonal antibody can prevent the occurrence of CIA. Injection of CCR7 monoclonal antibody into the successfully established CIA mouse model can significantly delay the progress of CIA. Moreover, it is reported that immune neutralization or knockout of CCR7 can also reduce the number of CD3+ naive T cells and increase the number of Treg cells, which protects against the joint destruction of CIA mice. The CCL21 knockout mice had a weakened response to infection. Preliminary researches shown that CCL21 is mainly responsible for the pathological function of CCR7 and increases cell chemotaxis (Aldahlawi et al., 2016). The recruitment of DCs, T/B cells to the specific sites in the lymph nodes is mediated by the actions of CCL21 and CCR7 , which have also been widely linked to RA progression. In plt/plt (lymph node T cell deficiency) mice lacking CCL21 expression, DC and T cells were unable to migrate to draining lymph nodes, and the T cell area tissues were altered. In addition to chemotactic activity, CCL21/CCR7 chemokine axis may also be closely related to the lymphoid follicular tissue in the RA synovium. Expression of CCL21 and CCR7 was higher in RA samples with germinal centers than that RA in samples without germinal centers, indicating that CCL21/CCR7 chemokine axis may contribute to the formation of germinal centers. The expression of CCL21 and CCR7 was significantly higher in RA patients than that in normal controls and patients with osteoarthritis, and CCL21 was found to increase the migration ability of osteoclasts and the activity of bone resorption, which depended on the effect of CCR7. These results suggest that the CCL21/CCR7 chemokine axis may play a crucial role in the occurrence and development of RA by regulating osteoclasts function (Pickens et al., 2011). Immunohistochemical examination found that CD45RA+ naive T cells infiltrated around the vessels of RA patients, and the expression of CCL21 was abnormally increased in the lesions. This suggests that CCL21 may be involved in the process of abnormal aggregation of naive T cells to inflammation sites in RA patients. The co-expression of CCR7 and CD95 in peripheral blood CD4+ T cells of patients with active RA was significantly higher than that of patients inactive RA and normal controls, and this expression level was positively correlated with the level of plasma IL-6 and the disease activity of RA, suggesting CCR7+CD95+CD4+ T cells are an important cell subset in the pathogenesis of RA. Meanwhile, it was also found that the expression of transcriptional CCR7 in RA monocytes and macrophages was closely correlated with patient’s disease activity score (DAS28). Immunohistochemical and ELISA results showed that CCL21 was also highly expressed in the synovial tissues of RA patients, and these highly expressed CCL21 was produced by fibroblasts and macrophages. CCR7 was also highly expressed in macrophages and the lining and sublining of endothelial cells in the synovial tissue of RA patients. Activation of CCR7+ endothelial cell migration can promote angiogenesis. Pannus formation is one of the important pathological manifestations of RA (Pickens et al., 2012). Studies have shown that CCL21 can induce the migration of human vascular endothelial cells (HMVEC) by combining with CCR7 at the joints of RA, which directly promotes angiogenesis. While antagonism of CCL21 or CCR7 inhibits HMVEC migration and reduce angiogenesis. Altogether, CCL21 indirectly triggers angiogenesis by activating RA fibroblasts and macrophages to secrete pro-angiogenic factors (such as vascular endothelial growth factor, angiopoietin-1 and interleukin-8), providing favorable evidences that CCL21/CCR7 chemokine axis mediates synovial angiogenesis. CCL21 has been reported to promote the proliferation and antigen presentation of bone marrow DCs in RA. CCR7+ DCs and T cells can be recruited into lymphoid and non-lymphoid tissues. These findings indicate that CCL21 stimulates immune cell migration and new blood vessel formation to synergistically accelerate the progression of RA disease (Li et al., 2017).
In addition to regulating immune cell infiltration, studies have shown that CCR7 is highly expressed on the surface of monocytes in the early stages of RA. With the development of RA, the level of CCR7 in RA synovial tissue macrophages was significantly increased. During RA progression, infiltrating macrophages are remodeled into M1-type macrophages, producing IL-6 and IL-23, and polarizing naive T cells into pathogenic Th17 cells. CCL21 promotes M1-driven Th17 cell differentiation, which promotes osteoclast production and initiates the destructive phase of the disease. Interestingly, IL-17 secreted by Th17 cells regulates CCR7 expression in RA fibroblasts and endothelial cells, indicating that there may be a feedback regulation between CCL21-induced Th17 polarization and the reactivity of RA fibroblasts and endothelial cells to CCL21. The combination of CCL21’s ability to mediate T cell accumulation, recruit bone marrow cells and activate the transcription of IL-6 and IL-23 can achieve crosstalk between macrophages and T cells, which is a necessary condition for CCL21 to drive Th17 polarization. Ultimately, this inflammatory environment cultured by CCL21 promotes osteoclast production (Van et al., 2020, Jiang et al., 2015). In summary, locally expressed CCL21 causes erosive arthritis by driving M1 and Th17 cells, while angiogenesis and progressive immune cell influx further accelerate the disease course of RA. Nevertheless, blocking the function of CCL21 eliminates monocyte infiltration in the early stage of RA and prevents M1 and Th17 cross-talk, which prevents the progression of joint inflammation and bone destruction in RA. Studies have shown that CCL21 is also highly expressed in RA synovial fluid, attracting circulating monocytes. CCL21 plays a vital role in the recruitment of CCR7+ monocytes in RA synovial fluid. CCR7 level on monocytes correlated with C-reactive protein (CRP) level. These findings not only indicate that CCL21 actively attracts monocytes to joints, but also that synovial macrophages remain key effector cells in CCL21-induced arthritis mice. These results suggest that CCL21/CCR7 chemokine axis may be a new target for the treatment of RA (Moschovakis et al., 2019).