CCL21/CCR7 chemokine axis participates in the pathological
process of SS by regulating the JNK and p38MAPK signaling pathways
The migration and continuous infiltration of lymphocytes are closely
related to the destruction of SS exocrine glands. A large number of
lymphocytes are focally infiltrated around the ducts of exocrine glands,
and the infiltrating lymphocytes are mainly T cells (Aiyegbusi et al.,
2021). Studies have found that CCR7 is highly expressed on the surface
of CD4+ and CD8+ T cells in the
peripheral blood of SS patients, and the chemotactic effect of CCL21 on
CD4+ T cells is stronger than that of
CD8+ T cells, indicating that the pathological changes
of a large number of CD4+ T cell infiltration may be
related to the abnormal expression of CCL21 and CCR7 in SS. This
suggests that CCL21/CCR7 chemokine axis may play an important role in
the pathogenesis of SS and participate in the immune response of SS. It
was reported that the migration of CD4+ T cells in the
peripheral blood of SS was significantly increased under the action of
CCL21, indicating that CCL21 can significantly increase the migration of
CD4+ T cells in SS (Mircheff et al., 2019). As shown
above, the expression of CCR7 on CD4+ T cells in
peripheral blood of SS patients was significantly increased, which was
due to the combination of CCL21 and CCR7 to induces actin agglutination
and pseudopodia formation in CCR7-expressing cells, promoting the
directed transfer of CCR7+ cells along the CCL21
concentration gradient, leading to an increase in the migration of
CD4+ T cells. This may be the mechanism of migration
and infiltration of CD4+ T cells in SS. However, after
treatment with CCR7 monoclonal antibody, the chemotactic index of
CD4+ T cells was significantly reduced, and there was
a significant positive correlation between the chemotactic index of
CD4+ T cells and the expression of CCR7 in SS
patients. The high expression of
CCL21 was detected in the salivary glands of SS patients, and the
expression of CCL21 was correlated with lymphocyte infiltration,
suggesting that there may be a positive feedback regulation mechanism in
the pathogenesis of SS. That is, under the action of the CCL21/CCR7
chemokine axis, a small amount of early lymphocytes migrate and
infiltrate to the salivary gland lobules, while the migrated lymphocytes
are activated and continue to express CCL21 and CCR7, which greatly
increases the number of infiltrated lymphocytes, thereby promoting the
development of SS (Tandon et al., 2017, Bunting et al., 2013, Carubbi et
al., 2014).
Previous studies reported that CD4+ T cells in
different groups were stimulated by CCL21 in vitro, and SP600125 and
SB203580, the specific blockers of JNK and p38MAPK signaling pathways,
were used to intervene on CD4+ T cells in peripheral
blood of SS patients. It was found that under the condition of no
stimulating factors, compared with the normal group, p-JNK and p-P38MAPK
were highly expressed in SS group, suggesting that there were abnormally
active p-JNK and p-P38MAPK signal transduction in CD4+T cells of SS patients, which may be related to the pre-activation state
of CD4+ T cells or the presence of certain cytokines
in plasma that can cause their activation in SS patients. These two
signaling pathways may be involved in mediating the occurrence and
development of SS. In CD4+ T cells stimulated by
CCL21, the expression of p-JNK and p-P38MAPK was significantly increased
in SS group compared with normal control group, suggesting that
CCL21/CCR7 chemokine axis can can
rapidly activate JNK and p38MAPK. This effect is more obvious in SS
patients. After adding CCR7 monoclonal antibody to block the interaction
between CCL21 and CCR7, the expression of p-JNK and p-P38MAPK on
CD4+ T cells in pSS
patients was significantly decreased. These results further demonstrated
that the activities of JNK and p38MAPK were related to the regulation of
CCL21/CCR7 chemokine axis. The chemotactic index of
CD4+ T cells was significantly decreased in JNK
pathway blocking group and p38MAPK pathway blocking group of SS,
suggesting that blocking these two pathways can significantly inhibit
the chemotactic effect of CCL21/CCR7
chemokine axis on the CD4+ T cell in SS patients.
These results suggest that JNK and p38MAPK pathways may mediate
lymphocyte migration induced by CCL21/CCR7
chemokine axis in SS. Moreover, it
was also found that the chemotactic index of p38MAPK pathway blocking
group was lower than that of JNK pathway blocking group in SS,
suggesting that the inhibitory effect of p38MAPK blocker on
CCL21/CCR7-induced lymphocytes migration was stronger than that of JNK
blocker in SS. This may be due to ”cross talk” between JNK and p38MAPK
pathways. In conclusion, CCL21/CCR7
chemokine axis, as an extracellular
signaling molecule, can activate JNK
and p38MAPK pathways in peripheral blood lymphocytes, and blocking the
activity of two pathways can significantly reduce the migration of
CD4+ T cells in SS, suggesting that JNK and p38MAPK
pathways play a crucial role in the signaling transmission process of
CCL21/CCR7 chemotactic CD4+ T cells, and opens up new
ideas for controlling the occurrence and development of SS (Mircheff et
al., 2015)(Figure 4).