CCL21/CCR7 chemokine axis participates in the pathological process of asthma through regulating NF-κB signaling pathway
The pathogenesis of asthma is very complex. Chemokines and their receptors, inflammatory cytokines and inflammatory signaling pathways play different important roles in different pathological stages of asthma (Alwarith et al., 2020). The combination of CCL21 and CCR7 regulates the activity of DCs or macrophages, presenting antigens and activating naive T cells. T cells secrete a large number of inflammatory cytokines when regulated by DCs, which directly or indirectly induce or aggravate the inflammatory immune response in asthma (Feng et al., 2021). Studies have also found that the number of CCR7+ T cells in the BALF of allergic asthma patients is significantly increased, and the expression of CCR7 is closely related to the pathological process of allergic asthma. Therefore, inhibiting the activity of CCL21 and CCR7 may help reduce the inflammatory response in asthma. The level of CCL21 was also significantly increased in BALF of asthma model mice, and the expression of CCR7 mRNA and CCR7 in lung tissue was significantly increased, indicating that CCL21/CCR7 chemokine axis may be one of the important factors of airway inflammation in asthma (Qi et al., 2018).
NF-κB plays a vital role in the regulation of inflammation and immune response. P65 and P50 are important members of the NF-κB family, which binds to their inhibitor protein IκB in inactive form in resting cells. Chemokines, cytokines and oxidative stress can activate and phosphorylate them, thus activating transcription and mediating inflammation response (Liu et al., 2016, Wei et al., 20168). The studies found that the expression of p-IκB and p-P65 in the lung tissue of mice in asthma model group was significantly increased, while the expression of p-IκB and p-P65 in the lung tissue of mice in asthma model group was significantly down-regulated by blocking NF-κB pathway. In addition, reports have shown that the interaction between CCL21/CCR7 and NF-κB can activate IκB, leading to NF-κB entry into the nucleus and enhancing its DNA-binding ability. Stimulation of DCs by CCL21 also leads to the activation of NF-κB, which mediates inflammation response. Taken together, these results suggest that CCL21/CCR7 chemokine axis may participate in the pathological process of asthma by regulating the NF-κB pathway. CCL21/CCR7 chemokine axis may also provide a new research direction for asthma prevention and treatment (Lou et al., 2021, Zhang et al., 2018)(Figure 4).
CCL21/CCR7 chemokine axis participates in the pathological process of ankylosing spondylitis by regulating Smads/Runx2 and Smads/osterix signaling Pathways
The main pathological features of ankylosing spondylitis (AS) are tendon attachment point lesions and ligament ossification. The blood macrophages of AS patients can produce high level of IL-23, and IL-23 plays a great role in promoting the systemic inflammation of AS. IL-23 can attachment point inflammation symptoms in Spondyloarthropathy by acting on T cells in AS attachment point. Additionally, IL-23 over-expression can cause infiltration of macrophages, T cells and neutrophils at the attachment point (Voruganti et al., 2020, Yu et al., 2020). Studies found that the mRNA expression of CCL21 was significantly increased in the ligament tissue of AS, suggesting that the macrophages and Th cells in the blood of AS as well as the macrophages and ligament fibroblasts in the tissue of the attachment point may be the source of CCL21. Secondly, the binding of CCL21 and CCR7 mediated the migration of synovial vascular endothelial cells and angiogenesis in RA, and the disorder of angiogenesis and heterotopic ossification are manifestations of AS attachment point lesions. IHC results showed that CCL21 and CCR7 were mainly expressed in the capillary wall of AS, and CCR7 was also highly expressed in ligament fibroblasts, suggesting that CCL21 might migrate to ligament tissue through capillaries. In addition, the capillary density in the ligament tissue of AS is much higher than that in the normal tissue, and combined with the function of CCL21 to promote angiogenesis, it is speculated that the high expression of CCL21 in the ligament tissue may be a vitalfactor that promotes the disorder of vascular formation in AS ligament. Taken together, these results suggest that CCL21/CCR7 chemokine axis may be involved in AS attachment point lesions and accelerate the process of angiogenesis disorder and heterotopic ossification (Sulicka et al., 2017).
Alkaline phosphatase (ALP) and integrin-binding salivary protein (IBSP) are early markers of ossification. Studies have found that different concentrations of CCL21 have different effects on ALP transcription level, but no significant change in IBSP expression. Osteocalcin (OCN), as a mid-stage marker of osteogenesis, was significantly up-regulated after 48h of treatment with CCL21, and the level of osteocalcin in the culture medium supernatant was also significantly increased on the sixth day of treatment. Meanwhile, the expression of Runx2 and osterix, the upstream regulators of ALP and OCN, was also increased significantly. These results suggested that CCL21 might promote osteogenic activity by regulating Runx2 and osterix expression. Additionally, studies have found that CCL21 can stimulate the synovial fibroblasts of RA and OA to secrete vascular endothelial grown factor (VEGF), and similar effects have been found in the ligament fibroblasts of AS. VEGF plays an momentous role in the ossification process and is also regulated by osterix. These resulte suggested that CCL21 might contribute to the occurrence of ossification through regulating Runx2 and osterix signaling pathway. At the same time, it was found that CCL21 level in serum and ligament tissues was increased in AS patients, and CCL21 could promote the ossification ability of ligament fibroblasts, which provided a basis for further studies on the roles of CCL21/CCR7 chemokine axis in AS (Qin et al., 2014)(Figure 4).