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).