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).