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).