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\begin{document}

\title{The Role of CCL21/CCR7 Chemokine Axis in Autoimmune Diseases Progression}



\author[1]{Le Han}%
\author[1]{Danlian Wu }%
\author[2]{Lingling Zhang}%
\affil[1]{Southeast University}%
\affil[2]{Anhui Medical University}%


\vspace{-1em}



  
  \date{May 30, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Autoimmune diseases are diseases characterized by local or systemic
abnormal inflammatory immune responses. With the in-depth exploration of
the pathological mechanism of autoimmune diseases, it is found that
occurrence and development of autoimmune diseases are largely related to
the interaction between chemokine receptors and chemokines expressed at
inflammatory sites. CCR7, one of Chemokine receptors members, binds to
CCL21, which regulates lymphocyte homing, neovascularization and immune
cells migration in autoimmune diseases. However, the underlying
signaling pathways of CCL21/CCR7 need to be further explored. Despite
the enormous advances in our knowledge of chemokines, research about the
involvement of CCL21/CCR7 in autoimmune diseases progression is still
limited. Thus, in this review, we summarize the essential role of
CCL21/CCR7 in autoimmune diseases progression. Further studies are
critical to illustrate the distinct roles of CCL21/CCR7 in autoimmune
diseases progression, and are important significance for discovery of
new biomarkers and drug targets of autoimmune diseases.%
\end{abstract}%



\sloppy


\textbf{The Role of CCL21/CCR7 Chemokine Axis inAutoimmune Diseases
Progression}

Le HAN\textsuperscript{1}, Danlian WU\textsuperscript{1}, Lingling
ZHANG\textsuperscript{2, 3, 4 *}

\textsuperscript{1} Department of Pharmacy, The Affiliated Jiangyin
Hospital of Southeast University Medical College, Jiangsu Province,
Jiangyin, China.

\textsuperscript{2} Institute of Clinical Pharmacology, Anhui Medical
University, Hefei,China

\textsuperscript{3} Key Laboratory of Anti-inflammatory and Immune
Medicine, Ministry of

Education, Hefei, China

\textsuperscript{4} Anti-inflammatory Immune Drugs Collaborative
Innovation Center, Anhui Province, Hefei, China

\textbf{*Corresponding Author:}

Prof. Ling-ling ZHANG. Institute of Clinical Pharmacology, Anhui Medical
University, Anhui, Hefei 230032, China

\emph{E-mail addres} s: \emph{ll-zhang@hotmail.com (L.L} . ZHANG);

Phone: +86-0551-6516-1206, Fax: +86-0551-6516-1208

The main body of the manuscript has 7932 characters.

\textbf{Abstract}

Autoimmune diseases are diseases characterized by local or systemic
abnormal inflammatory immune responses. With the in-depth exploration of
the pathological mechanism of autoimmune diseases, it is found that
occurrence and development of autoimmune diseases are largely related to
the interaction between chemokine receptors and chemokines expressed at
inflammatory sites. CCR7, one of Chemokine receptors members, binds to
CCL21, which regulates lymphocyte homing, neovascularization and immune
cells migration in autoimmune diseases. However, the underlying
signaling pathways of CCL21/CCR7 need to be further explored. Despite
the enormous advances in our knowledge of chemokines, research about the
involvement of CCL21/CCR7 in autoimmune diseases progression is still
limited. Thus, in this review, we summarize the essential role of
CCL21/CCR7 in autoimmune diseases progression. Further studies are
critical to illustrate the distinct roles of CCL21/CCR7 in autoimmune
diseases progression, and are important significance for discovery of
new biomarkers and drug targets of autoimmune diseases.

\textbf{Key words:} CCL21, CCR7, Cell Migration, Autoimmune Diseases,
Signaling Pathway

\textbf{Abbreviations}

AS, ankylosing spondylitis; CDK, cyclin dependent kinase; CRP,
C-reactive protein; DAG, diglyceride; DCs, endothelial cells; DMARDs,
disease modifying anti-rheumatic drugs; ESR, erythrocyte sedimentation
rate; FS, focal index; GPCRs, G-protein-coupled receptors; GSK3,
glycogen synthase kinase 3; HMVEC, human vascular endothelial cells; NK,
Natural killer; PI3K, phosphatidylinositol-3-OH kinases; RA, rheumatoid
arthritis; RF, rheumatoid factor; SLE, systemic lupus erythematosus;
SSc, systemic sclerosis; VEGF, vascular endothelial grown factor.

\par\null

\textbf{Introduction}

Autoimmune diseases are characterized by immune responses to
self-antigens that result in tissue damage. Autoantibodies directed
against normal host antigens are a common feature of many autoimmune
diseases (Liang et al., 2017). Autoimmune diseases mainly include
diffuse connective tissue diseases (such as rheumatoid arthritis, (RA),
systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sj\selectlanguage{ngerman}ögren
Syndrom (SS), etc.), spondylitis-related arthritis (ankylosing
spondylitis, AS) and infection-related arthritis, tenosynovitis and
bursitis. Autoimmune diseases are the frequent disorder, however, its
etiology and pathogenesis are still not completely understood (Han et
al., 2020). The clinical manifestations and immune processes of affected
tissues and organs are also different, but the common point is the
deficiency of immune regulation. At present, treatment of autoimmune
diseases has two goals: the first is to symptom relief and functional
maintenance, and the second is to delay the process of tissue damage.
Therapeutic drugs are mainly divided into non-steroidal
anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs
(SAIDs) and disease modifying anti-rheumatic drugs (DMARDs) (such as
chemical drugs, natural drugs and biological agents) (Zhang et al.,
2020). With the further elucidation of the pathological mechanism of
autoimmune diseases and the exploration of new drug targets, it has been
found that cytokines, cell surface molecules and their mediated signal
pathways are involved in immune cell dysfunction and the pathological
process of autoimmune diseases (Xiao et al., 2021).

The chemokines comprise a large family of low molecular weight (8--10
kDa) cytokines, with chemotactic and pro-activatory effects on different
leukocyte lineages (Griffith et al., 2014). It plays an important role
in lymphocytes homing and cell differentiation, immune response,
inflammatory response, wound repair and tumor cell metastasis ('Agostino
et al., 2020). Chemokines are classified into 4 main families based on
the position of conserved cysteine residues within their N-terminal
region; CXC, CC, CX3C, and C chemokines. Chemokine receptors are GPCRs
regulated by small protein ligands known as chemokines, which are
8--10\selectlanguage{english} kDa proteins with a globular core structure stabilized by 1--2
conserved disulfide bridges1 (Wasilk et al., 2020). Chemokine receptors
are a seven membrane-spanning domain, which regulates chemotaxis and
effector functions of T-lymphocytes, macrophages, and dendritic cells.
According to the types of chemokine binding, chemokine receptors can
also be divided into four subfamilies: CXCR, CCR, XCR and CX3CR. Much of
membrane signaling is mediated by ligand binding to specific receptors.
These receptors bind to diverse ligands and evoke different effector
systems (Worbs et al., 2020)(Figure 1).

Chemokines interact with chemokine receptors in a promiscuous network,
such that each receptor can be activated by multiple chemokines. Actions
of chemokines through chemokine receptor signaling leads to an array of
diverse functions in different tissue compartments (Cardona et al.,
2008, Hons et al., 2018). Under the regulation of chemokines and their
receptors system, immune cells are involved in a variety of
physiological and pathological processes, such as the reconstruction of
the cytoskeleton structure, migration and infiltration into target
organs, mediated stress response, infection, wound healing, T cells
differentiation, lymphoid organ development, angiogenesis, tumor cells
metastasis and DCs maturation (Ridiandries et al., 2018). Different
cells express the different types of chemokines and receptors. Thus,
they have different functions on different cells. When chemokine binds
to their receptor, various combinations of intracellular signaling
pathways are activated. Receptor-ligand interaction leads to signal
transduction involving G-proteins which promotes the release of
intracellular second messengers such as calcium, cyclic adenosine
monophosphate (cAMP) and phosphoinositides (Laufer et al., 2018). This
results in the expression of several genes and activates a signaling
cascade that, depending on the context, can stimulate cellular growth,
migration, pseudopodia formation, adhesion, as well as angiostasis. Some
chemokine systems have been reported to promote or inhibit tumors by
driving immune cells or directly participating in tumor activities.
Additionally, the chemokine/receptor systems also play a key role in the
pathogenesis of autoimmune diseases by regulating the biological
functions of immune cells. Chemokines and their receptors not only
regulate the migration of immune cells during inflammation, but also
closely related to the formation of lymphoid tissues, maturation and
transport of immune cells (Comerford et al., 2013). Altogether,
chemokines and their receptors are not only abnormally expressed in
tumors, but also closely related to the pathological process of
autoimmune diseases (Tripathi et al., 2020). This article reviews the
research progress of chemokines and their receptors in autoimmune
diseases. The aim is to provide the new insights and find new targets
for the treatment of autoimmune diseases.

\textbf{Biological characteristics of CCL21/CCR7chemokine axis}

\textbf{Construction, source, distribution and expressionof CCL21/CCR7
chemokine axis}

CCL21\selectlanguage{english},one of the chemokines of CC family, is a small molecular protein
with the function of chemotactic cell migration. CCL21 is one of the
only two ligands of CC-Chemokine receptor 7 (CCR7) (the other being
CCL19) (Salem et al., 2021). The distribution positions of these two
ligands is overlaping and distinct. Both of them are expressed in
stromal cells of T-cell-rich lymph node regions, and mainly perform cell
migration function (Forster et al., 2008). CCR7 is a GPCR commonly
expressed by T-cell subset centra memory cells, thymic T-cells, B cells,
mature DCs and other rare cell subsets such as
CD4\textsuperscript{+}CD25\textsuperscript{+} splenocytes. CCL21/CCR7
chemokine axis plays a vital role in the homing of lymphocytes to
secondary lymphoid tissues. CCL21 have chemotactic effect on a variety
of immune cells, including DCs, T/B cells and Natural killer (NK) cells
( Stone MJ et al., 2017, Nagarsheth et al., 2017). Like other chemokine
receptors, CCR7 is a seven-fold transmembrane G-protein-coupled receptor
with seven \selectlanguage{english}a-helical transmembrane structures rich in hydrophobic amino
acids. The N-terminal is located on the outside of cell, which
determines the specificity of ligand binding. CCR7 was expressed on the
surface of B cells, naive T cells, memory T cells, activated NK cells
and DCs. In addition, the expression of CCR7 could also be detected in
various lymphoid tissues (Tutunea-Fatan et al., 2015, Cai et al., 2017).

The chemotactic effect of CCL21 is realized through its receptor CCR7,
and the intensity of the effect is determined by the expression level of
CCR7 on immune cells (Goto et al., 2017). When CCL21 binds to CCR7
expressed on target cell, it promotes the aggregation of integrin on the
cell surface, activates the cytoplasmic conjugated G protein. GDP is
replaced by GTP that binds to the a \selectlanguage{english}subunit, which forms a free \selectlanguage{greek}βγ
\selectlanguage{english}dimer. \selectlanguage{greek}βγ \selectlanguage{english}dimer activates enzymes in two main signaling pathways:
phospholipase C\selectlanguage{greek}β\selectlanguage{english}2, phospholipase C\selectlanguage{greek}β\selectlanguage{english}3 (PLC\selectlanguage{greek}β\selectlanguage{english}2 and C\selectlanguage{greek}β\selectlanguage{english}3) and
phosphatidylinositol-3-OH kinases (PI3K). Activated by PLC, inositol
hexaphosphate on the cell membrane is hydrolyzed to produce inositol
triphosphate (IP3) and diglyceride (DAG). IP3 promotes the release of
intracellular stored calcium which causes a rapid increase in
intracellular calcium ion concentration, thereby inducing rapid
Ca2\textsuperscript{+} mobilization of tyrosine kinases (such as MAPK,
FAK(including PI3K and JAK, etc.)), PKC, and GTPase phosphorylation (Shi
et al., 2015, Mollica et al., 2019, Singh et al., 2017, Hauser et al.,
2016). Signal transduction could be stimulated in various ways to change
the recombination of intracellular skeletal proteins, such as actin
polymerization. With the extension and retreat of pseudopodia, it can
cause the movement of target cells which produces efficient chemotaxis.
A considerable body of evidence suppoorts that the high-affinity binding
of CCL21 and CCR7 regulates a series of signal transducments that exert
a strong chemotactic effect on B cells, T cells, NK cells and DCs
(Vanden , 2014).

CCL21/CCR7 chemokine axis was also reported to be highly expressed on
the surface of various tumor cells. While the over-expression of CCR7 is
correlated with the metastasis of cancer cells from non-small cell lung
cancer, breast cancer, squamous cell carcinoma of the head and neck,
colorectal cancer, prostate cancer, esophageal squamous cell carcinoma
and gastric cancer to lymph nodes (Zhong et al., 2017). The specific
binding of CCL21 and CCR7 promotes the migration, proliferation and
anti-apoptosis of tumor cells, thus affecting the occurrence and
development of tumors. Previous studies have proved that CCL21/CCR7
chemokine axis can not only promote the proliferation and metastasis of
tumor cells, but also promote the differentiation and migration of
immune cells (Park et al., 2015, Joutoku et al., 2019, Xiong et al.,
2017, Chen et al., 2015). CCL21/CCR7 chemokine axis is also widely
expressed in non-lymph node tissues such as fibroblasts and smooth
muscle nuclear endothelial cells, and is closely related to biological
effects such as inflammation, smooth muscle cell proliferation and
matrix remodeling. The specific binding of CCL21 and CCR7 can also
promote the migration of naive T cells and effector T cells to
inflammation and infection sites and promotes the interaction of memory
T cells, naive T cells and DCs in lymph nodes, which enhances the
effective activation of DCs to antigen-specific T cells. In addition to
inducing chemotaxis, CCL21 can also stimulate the proliferation of
CD4\textsuperscript{+}/CD8\textsuperscript{+} T cells and promote Th1
cell polarization (Luo et al., 2016, Stacer et al., 2016). These studies
show that CCL21 can not only chemotactic T cells to the lesion sitee,
stimulate the proliferation and differentiation of T cells, but also
mediate lymphatic metastasis. Taken together, the CCR7-mediated cell
migration underlies a broad range of immune system activities and
therefore it is important to understand its mechanism. CCL21/CCR7
chemokine axis may provide a new perspective for clinical treatment
(Dong et al., 2017, Xia et al., 2015)(Figure 2).

\textbf{Biological functions of CCL21/CCR7 chemokine axis}

\textbf{Chemotaxis of CCL21/CCR7chemokine axis}

Chemotaxis is the most important function of CCL21/CCR7 chemokine axis
in adaptive immunity (Nomiyama et al., 2013). The specific binding of
CCL21 to its receptor CCR7 can mediate the homing of DCs and T
lymphocytes to the secondary lymphoid tissues, and guide the directional
movement and aggregation of T cells in the secondary lymphoid.
CCL21/CCR7 chemokine axis can promote the migration of mature DCs from
peripheral tissues to regional lymph nodes, and enhance the phagocytosis
of mature DCs to different antigens (Ruytinx et al., 2018). DCs are a
powerful antigen presenting cell. Immature DCs are highly active, can
effectively absorb and process antigens, and locate the processed
antigens to non-lymphoid tissues. After exposure to active signals, DCs
mature and enter lymphatic tissues. Because CCL21 plays a vital role in
the migration and functional maturation of DCs ( Ruez et al., 2018,
Antonelli et al., 2014). Additionally, CCL21 was highly espressed in
lymphatic epithelial cells, which combined with CCR7 to facilitate the
entry of mature DCs into lymphatic vessels. Mature DCs entering the
lymphatic vessels can be located in the T lymphocyte area under the
action of CCL19. Nevertheless, CCL21 has chemotactic effect only on
mature DCs and has no chemotactic effect on immature DCs. CCL21 binds to
CCR7 expressed on mature DCs, which exerts biological effects by
inducing the mobilization of calcium ions in mature DCs (Averbeck et
al., 2017). Previous studies have reported that the combination of CCL21
and CCL19 with CCR7 is both different and competitive. Physiological
concentration of CCL21 shows chemotactic effect on peripheral blood T
cells, but CCL19 does not. This is due to the different affinity of
CCL21 and CCL19 with CCR7. In the presence of CCL21, T cells move away
from CCL19 and toward CCL21, which reflects the competitive relationship
between CCL21 and CCL19. However, both of these ligands can induce the
migration of B cells and tumor cells through different signal
transduction (Yu et al., 2015).

\textbf{Cell adhesion and integration capabilities of CCL21/CCR7
chemokine axis}

CCL21/CCR7 chemokine axis has the ability to promote cell adhesion and
affinity to varying degrees. Previous studies have found that CCL21/CCR7
chemokine axis can enhance the adhesion properties of glomerular
mesangial cells through mediating glycogen synthase kinase 3 (GSK3) and
Akt pathways (Li et al., 2011). CCL21/CCR7 chemokine axis can also
promote the metabolism, adhesion and anti-apoptotic processes of various
tumor cells. In metastatic squamous cell carcinoma of the head and neck,
CCL19/CCR7 chemokine axis promotes the migration of tumor cells by
regulating \selectlanguage{greek}β\selectlanguage{english}\textsubscript{1} integrin expression. Subsequently, studies
have also discovered that integrin \selectlanguage{greek}α\selectlanguage{english}v\selectlanguage{greek}β\selectlanguage{english}3, a new signaling molecule, is
involved in the process of tumor cell migration through CCL19/CCR7
chemokine axis. These signaling molecules initiate the process of cell
adhesion and migration through the interaction with the CCL21/CCR7
chemokine axis (Zhang et al., 2018).

\textbf{Effect of CCL21/CCR7 chemokine axis on cell growth}

CCL21/CCR7 chemokine axis can affect cell proliferation by mediating
different signaling pathways. Early studies have shown that CCL21 can
affect the biological activity of hematopoietic progenitor cells by
inhibiting their proliferation. Additionally, CCL21/CCR7 chemokine axis
can also affect the proliferation of glomerular mesangial cells,
CD4\textsuperscript{+} T cells, CD8\textsuperscript{+}T cells and
CD34\textsuperscript{+}cells in bone marrow through different signals
(Zhang et al., 2016). It was also proved that CCL21/CCR7 chemokine axis
inhibits T cell proliferation by slowing down the degradation of cyclin
dependent kinase (CDK) inhibitors and down-regulating the activity of
CDK1 (Kuwabara et al., 2012). A recent investigations found that
CCL21/CCR7 chemokine axis stimulated the proliferation of DCs in bone
marrow through phosphorylating NF-\selectlanguage{polish}ĸ\selectlanguage{english}B65. These results provide a new
entry point for studying the function of CCL21/CCR7 chemokine axis in
terms of proliferation (Korbecki et al., 2020, Li et al., 2020).

\textbf{Other functions of CCL21/CCR7} \textbf{chemokine axis}

In addition to the above functions, CCL21/CCR7 chemokine axis has a
certain effects on cell differentiation, survival, endocytosis,
migration rate and invasion ability. Studies have suggestted that the
binding of CCL21 and CCR7 can significantly affect the internal
structure and migration rate of renal DCs and blood T cells (Luo et al.,
2020, Legler et al., 2016). And different concentrations of CCL21
produced different chemotactic rates for renal DCs and blood T cells.
The functional diversity of CCL21/CCR7 chemokine axis in the immune
process also provides the basis for participating in the occurrence and
development of autoimmune diseases. With the continuous in-depth study
of CCL21/CCR7 chemokine axis, the role of CCL21/CCR7 chemokine axis has
attracted more and more attention from domestic and foreign scholars in
autoimmune diseases (Rong et al., 2017, Zlotnik et al., 2012, Sokol et
al., 2015).

\textbf{CCL21/CCR7 chemokine axis regulates the pathological process of
autoimmune diseases}

\textbf{CCL21/CCR7 chemokine axis and RA}

The pathogenesis of RA is related to the abnormal activation of T and B
cells. Activated CD4\textsuperscript{+} T cells differentiate into
special effector cells, which plays a essential role in specific immune
responses. A large number of activated CD4\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+}CD95\textsuperscript{+}CD4\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+}
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\textsuperscript{+} 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).

\textbf{CCL21/CCR7 Chemokine Axis and SS}

The main pathological manifestations of SS are dry eyes and xerostomia
caused by the infiltration of lymphocytes into lactear and salivary
glands. The pathogenesis of SS is based on the dysfunction and
infiltration of lymphocytes, accompanied by the production of
auto-antibodies and hypergamma globulinemia. The study found that the
expression of CCR7 was detected on the surface of CD4\textsuperscript{+}
and CD8\textsuperscript{+} T cells in the peripheral blood of patients
with SS. Compared with the CD4\textsuperscript{+} and
CD8\textsuperscript{+}T cells in the normal control, the expression of
CCR7 was significantly increased in SS. Compared with peripheral blood T
cells in SLE patients, CD4\textsuperscript{+} T cells in SS patients
express more CCR7, suggesting that CCR7\textsuperscript{+}
CD4\textsuperscript{+} T cells may play a key role in the pathogenesis
of SS (Argyropoulou et al., 2018). Transwell showed that under the
action of CCL21, the migration number of CD4\textsuperscript{+} T cells
in peripheral blood of SS patients was significantly higher than that of
the normal control, and the number of
CCR7\textsuperscript{+}CD4\textsuperscript{+} T cells was significantly
higher than that of CCR7\textsuperscript{+}CD8\textsuperscript{+} T
cells, indicating that CCL21 can significantly improve the migration
ability of CD4\textsuperscript{+} T cells in SS patients, and the
chemotaxis ability of CCL21 to CD4\textsuperscript{+} T cells may be
stronger than CD8\textsuperscript{+} T cells. This is because the
combination of CCL21 and CCR7 induces actin aggregation and pseudopodia
formation in CCR7-expressing cells and promotes the migration of
CCR7\textsuperscript{+} cells along the ligand concentration gradient,
which leads to the increase of CD4+T cell migration in the peripheral
blood of SS patients. This may be the mechanism by which the CCL21/CCR7
chemokine axis in SS participates in the migration and infiltration of a
large number of lymphocytes, especially CD4\textsuperscript{+} T cells.
Previous studies have been reported that the chemotaxis index of
CD4\textsuperscript{+} T cell in SS patients decreased significantly
after anti-CCR7 monoclonal antibody treatment. Correlation analysis
showed that there was a significant correlation between the chemotactic
index and CCR7 expression on CD4\textsuperscript{+} T cells in
peripheral blood of SS patients. These results further confirm that CCR7
plays a crucial role in the migration of CCL21 chemotactic lymphocytes
to specific tissues (Rischmueller et al., 2016). Analysis of
CD4\textsuperscript{+} T cell migration in SS patients and clinical data
showed that the chemotactic index of CD4\textsuperscript{+}T cell was
positively correlated with disease activity index, but there was no
significant correlation with the disease damage index. The results
indicated that the increased expression of CCR7 on the surface of
CD4\textsuperscript{+} T cells in the peripheral blood of SS patients
promoted the migration and infiltration of CD4\textsuperscript{+}T cells
to inflammatory sites. CCR7\textsuperscript{+} T cells migrate to
specific tissues under the action of CCL21, which inhibits cell
apoptosis, prolongs cell survival time and participates in the
occurrence and development of SS by activating corresponding signal
transducting pathways (Barone et al., 2005).

The prominent manifestation of abnormal humoral immunity in SS is
hyperglobulinemia, which occurs in more than 90\% of patients. The
increase of IgG level was the most obvious. Meanwhile, hyperglobulinemia
can promote erythrocyte sedimentation rate (ESR), and the levels of ESR
and IgG are closely related to the degree of disease activity in SS.
Studies have shown that the expression of CCR7 on
CD4\textsuperscript{+}T cells in SS patients is positively correlated
with the levels of ESR and serum IgG. The expression of CCR7 on
CD4\textsuperscript{+} T cells and the clinical manifestations in SS
patients showed that the expression of CCR7 was positively correlated
with the disease activity index. These results further demonstrate that
the expression of CCR7 on CD4\textsuperscript{+} T cells is closely
related to the disease activity of SS, and it is expected to be a new
indicator for monitoring the disease activity of SS (Bombardieri et al.,
2012). However, there is no significant correlation between the CCR7
level and the disease injury index, indicating that although CCR7 plays
an important role in the pathogenesis of SS, but it is not a key factor
in assessing disease severity. Taken together, the abnormally increased
expression of CCR7 on CD4\textsuperscript{+}T cells in SS peripheral
blood may play a key role in the abnormal accumulation of lymphocytes to
the affected glands to form lymphocytic infiltrating foci. Some scholars
reported that high expression of CCL21 was detected in the salivary
glands of SS patients, and the expression of CCL21 was related to
lymphocyte infiltration. The expression of CCL21 was also correlated
with the increased level of ESR, IgG, rheumatoid factor (RF), anti-SSA
antibody and anti-SSB antibody. The focal index (FS) and disease
activity index of SS were also correlated with the expression of CCL21.
CCL21/ CCR7 chemokine axis is expected to be a new indicator for
monitoring SS disease activity and predicting prognosis (Lee et al.,
2017). However, the expression of CCR7 on CD4\textsuperscript{+} T cells
was not associated with the degree of impairment of salivary and lacrist
gland function. This also indicated that the pathological changes of a
large number of CD4\textsuperscript{+} T cell infiltration in SS
exocrine glands may be related to the abnormal expression of CCR7 on T
lymphocytes of SS patients, which indirectly proved that CCR7 plays an
important role in the abnormal aggregation of T cells into diseased
tissues. T cells accumulate to the inflammation site, and the apoptosis
of infiltrating T cells is inhibited under the regulation of CCR7,
leading to the continuous and gradual enhancement of the inflammatory
response, which may partly explain the reason why the high expression of
CCR7 T cells are closely related to disease activity. In conclusion, the
CCL21/CCR7 chemokine axis may be one of the momentous links in the
pathogenesis of SS, and blocking the interaction of CCL21-CCR7 may have
positive significance for the control of SS disease progression.
Therefore, monoclonal antibodies against CCR7 and small molecule
compounds that inhibit the binding of CCL21 to CCR7 are highly likely to
be new therapeutic approaches for SS in the future (Psianou et al.,
2018).

\textbf{CCL21/CCR7chemokine axis and SLE}

The main characteristics of SLE are auto-antibodies formation, multiple
organs damage and multiple clinical inflammatory manifestations.
Increasing evidences suggest that the infiltration of T cells and white
blood cells into inflammatory tissues may play a key role in organ
involvement of SLE (Fanouriakis et al., 2021). Chemokines and their
receptors can migrate white blood cells to inflammatory sites, initiate
T cell immune response and regulate the differential recruitment of Th1
and Th2 cells. At present, many studies have shown that the abnormal
expression of CCL21 and CCR7 is closely related to SLE (Odler et al.,
2017). The expression of CCL21 in peripheral blood may be a biomarker of
lung involvement in SLE patients, as CCL21 and CCR7 have been identified
as key participants in the progression of pulmonary fibrosis. CCR7 is
expressed on lung fibroblasts and is important for the activation,
survival and proliferation of lung fibroblasts (Watanabe et al., 2008).
Moreover, It was found that CCL21 could not induce the migration of
CD4\textsuperscript{+} and CD8\textsuperscript{+} T cells in normal
body, could induce moderate migration of CD4\textsuperscript{+} and
CD8\textsuperscript{+} T cells in inactive SLE patients, and could
induce strong chemotactic movement of CD8\textsuperscript{+} T cells in
active SLE patients. The expression of CCR7 on CD8\textsuperscript{+} T
cells in the peripheral blood of active SLE patients was significantly
higher than that of inactive SLE patients and normal control. The level
of CCR7 mRNA on CD8\textsuperscript{+} T cells of active SLE patients
was significantly increased, and was significantly positively correlated
with SLE disease activity index score (Wieczorek et al., 2010).

The number of
CD4\textsuperscript{+}CD95\textsuperscript{+}CCR7\textsuperscript{+}cells
in active and inactive SLE patients was significantly higher than that
in normal control, the number of
CD4\textsuperscript{+}CD95\textsuperscript{+}CCR7\textsuperscript{-}cells
in active SLE patients was higher than that in the inactive SLE patients
and normal control, the number of
CD4\textsuperscript{+}CD95\textsuperscript{-}CCR7\textsuperscript{+}cells
in SLE patients was lower than that in normal control, indicating that
CD4\textsuperscript{+}CD95\textsuperscript{+}CCR7\textsuperscript{+}cells
were associated with auto-antibody reactions, while
CD4\textsuperscript{+}CD95\textsuperscript{+}CCR7\textsuperscript{-}cells
were closely related to were inflammatory response. However, CCR7
monoclonal antibody can completely block the chemotaxis of
CD8\textsuperscript{+} T cells induced by CCL21 in active SLE patients,
suggesting that high expression of CCR7 on CD8\textsuperscript{+} T
cells may be related to SLE activity. In summary, these results
demonstrate thatCCL21/CCR7 chemokine axis plays a crucial role in the
pathogenesis of SLE, and can provide an important reference for
monitoring the disease activity of SLE (Xu et al., 2012).

\textbf{CCL21/CCR7chemokine axis andpolymyositis}

The self-invasive of CD8\textsuperscript{+} T cells is the basis of
polymyositis (PM), and the main clinical manifestations are muscle
damage in the proximal extremities. The number of activated T cells in
the peripheral blood of PM patients increased significantly and moved to
the local area of myositis (Cerezo et al., 2020). A large number of
infiltrating cells, mainly CD8\textsuperscript{+} cytotoxic T
lymphocytes and macrophages, were found in myocytes and subintima of PM.
CD4\textsuperscript{+}T cells were found in the perineal and
perivascular regions. Immunohistochemistry and RT-PCR tests showed that
the expression of CCL21 was found in the muscles of PM, and CCR7
expression was detected in infiltrating monocytes in the endomysium of
PM.

Around the non-necrotic muscle tracts, more than half of
CD8\textsuperscript{+} T cells expressed CCR7, and the phenotype of
these cells was mostly
CD45RO\textsuperscript{+}CCR7\textsuperscript{+}CD\textsuperscript{+}8 T
cells. A few monocytes, muscle fibers and vascular endothelium showed
the immune activity of CCL21. These results suggested that the
interaction between CCL21 and CCR7 may play a vital role in the
pathogenesis of PM (Kuwabara et al., 2009). Since CCL21 mRNA is only
weakly expressed in normal muscle tissues, while CCR7 mRNA is not
expressed in normal muscle tissues, suggesting that the expression of
CCL21 and CCR7 may be pathologically up-regulated in PM. Double
immunostaining showed that a large number of CD8\textsuperscript{+} T
cells in the endomysium expressed CCR7, and
CCR7\textsuperscript{+}memory T cells may infiltrate the endomysium of
PM. Studies have found that CCR7\textsuperscript{+} memory T cells
closely surrounded the muscle fibers expressing MHC I class. There could
be multiple explanations for these findings. The first possibility is
that CCR7 may be expressed on auto-invasive CD8\textsuperscript{+} T
cells in PM. The second possibility is that CCR7\textsuperscript{+}
memory T cells may respond to the antigens presented by muscle fibers,
or some CCR7\textsuperscript{+} T cells may be naive T cells that are
sensitized for the first time at the lesion (Lv et al., 2018).

Studies have found that the immunohistochemical expression of CCL21 in
inclusion body myositis and dermatomyositis is different from that in
PM, which may be a different pathological mechanism of the disease.
Low-intensity expression of CCL21 and CCR7 was also detected by
immunohistochemistry or RT-PCR in control diseases without inflammation
(Rider et al., 2016). Like other chemokine systems, CCL21/CCR7 chemokine
axis is multifunctional and may not only participate in immune cell
recruitment, but may also participate in tissue homeostasis. Further
study of the effect of chemokines on muscle fibers may help us
understand the pathogenesis of PM and develop specific immunomodulatory
therapies (Chen et al., 2015). A series of research results have
indicated that the CCL21/CCR7 chemokine axis plays an important role in
the pathogenesis of PM. These findings, together with our data on the
up-regulation of CCL21/CCR7 chemokine axis, strongly suggest that
CCL21/CCR7 chemokine axis may play an important role in monocytes
recruitment and muscle tissue damage in PM (De et al., 2009, Miller et
al., 2013).

\textbf{CCL21/CCR7 chemokine axis and other diseases}

In addition, CCL21/CCR7 chemokine axis are is closely related to
autoimmune diseases such as SSc, vasculitis and osteoarthritis (OA)
(Ciccia et al., 2017). Studies have found that CCL21/CCR7 chemokine axis
can affect the connective tissue immune disorders of heart, lung, kidney
and digestive tract in SSc. In early studies, the differences between
children and adults with SSc showed that the number of resting
regulatory T cells was decreased and the number of
CD45RA\textsuperscript{+}CD4\textsuperscript{+}T cells was increased in
children compared with adults, but
CD45RA\textsuperscript{+}CD4\textsuperscript{+}T cells were
characterized by high expression of CCR7. This change in T cell
expression is conducive to initiating the activation of
CCR7\textsuperscript{+}CD4\textsuperscript{+} effector T cells in
adolescent SSc (Gonzalez et al., 2019). In vasculitis, CCR7 has
attracted much attention as a marker of B cells and memory T cells
differentiation. Moreover, CCR7 was also found to be expressed in
synovial tissues and synovial fibroblasts, which provided the basis for
CCCL21/CCR7 chemokine axis and local lesions (Hoffmann-Vold et al.,
2018). OA is also a major category of autoimmune diseases, and immune
dysfunction plays a crucial role in the pathogenesis of OA. Therefore,
the role of CCCL21/CCR7 chemokine axis in OA should not be ignored
(Favero et al., 2019)(Figure 3).

\textbf{CCL21/CCR7 chemokine axis participates in the occurrence and
development of autoimmune diseases by regulating related signal
pathways}

\textbf{CCL21/CCR7 chemokine axis participates in the pathological
process of RA through regulating the PI3K signaling pathway}

Angiogenesis is one of the main pathological features of RA, which
depends on the activation, migration and proliferation of endothelial
cells. Accordingly, inhibition of angiogenesis may provide a new
therapeutic approach for RA (MacDonald et al., 2018). Studies have found
that CCL21 and CCR7 were co-expressed on the endothelial cells of
synovial tissue. CCL21 can induce fibroblasts, macrophages and synovial
lining cells to produce pro-angiogenic factors in RA. Altogether, the
expression of CCL21 and CCR7 in RA blood vessels was linearly
correlated, suggesting that the CCCL21/CCR7 chemokine axis plays a vital
role in RA angiogenesis. Some studies have also shown that the
combination of CCL21 and CCR7 can induce HMVECs migration in the joints
of RA patients, but CCL19 has no effect on HMVECs migration. It may be
that CCL21 and CCL19 mediate different signal pathways (Hayashi et al.,
2009).

CCL21 was found to promote neovascularization at detectable
concentrations in RA joints. However, CCL21 promotes angiogenesis by
recruiting the accumulation of endothelial cells and endothelial
progenitor cells in RA synovial fluid and tissues. Further studies have
revealed that the binding of CCL21 to CCR7 regulates HMVEC migration and
angiogenesis by mediating the activation of PI3K pathway. In vitro
studies found that ERK, AKT1 and PI3K were the first to be
phosphorylated by CCL21 in HMVEC treated with CCL21 for different
durations, while JNK was activated last. However, blocking the ERK and
JNK pathways had no effect on the chemotaxis of CCL21-induced HMVEC.
Blocking the PI3K and AKT1 pathways can reduce the chemotaxis of CCL21
(Jiang et al., 2008, Van et al., 2020). Blocking PI3K pathway can also
reduce CCL21-mediated angiogenesis by 35-40\%, while blocking ERK and
JNK pathways had no effect on angiogenesis. These results indicate that
CCL21 may induce HMVEC chemotaxis through mediating PI3K and AKT1
pathways, and blocking PI3K pathway can reduce the regulatory effect of
CCL21 on HMVEC chemotaxis and angiogenesis. In conclusion, blocking PI3K
pathway can inhibit endothelial cells migration and angiogenesis induced
by the CCCL21/CCR7 chemokine axis in RA. These findings suggest that
inhibition of angiogenesis may provide a new idea for the treatment of
RA, and CCL21/CCR7 chemokine axis may also be a new target for the
treatment of RA (Cuesta-Mateos et al., 2010, Calabresi et al.,
2018)(Figure 4).

\textbf{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\textsuperscript{+} and CD8\textsuperscript{+} T cells in the
peripheral blood of SS patients, and the chemotactic effect of CCL21 on
CD4\textsuperscript{+} T cells is stronger than that of
CD8\textsuperscript{+} T cells, indicating that the pathological changes
of a large number of CD4\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} T cells in SS (Mircheff et al., 2019). As shown
above, the expression of CCR7 on CD4\textsuperscript{+} 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\textsuperscript{+} cells along the CCL21
concentration gradient, leading to an increase in the migration of
CD4\textsuperscript{+} T cells. This may be the mechanism of migration
and infiltration of CD4\textsuperscript{+} T cells in SS. However, after
treatment with CCR7 monoclonal antibody, the chemotactic index of
CD4\textsuperscript{+} T cells was significantly reduced, and there was
a significant positive correlation between the chemotactic index of
CD4\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+}T cells of SS patients, which may be related to
the pre-activation state of CD4\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} T cells in
SS, suggesting that JNK and p38MAPK pathways play a crucial role in the
signaling transmission process of CCL21/CCR7 chemotactic
CD4\textsuperscript{+} T cells, and opens up new ideas for controlling
the occurrence and development of SS (Mircheff et al., 2015)(Figure 4).

\selectlanguage{greek}\textbf{CCL21/CCR7 chemokine axis participates in the pathological
process of asthma through regulating NF-κB signaling pathway}\selectlanguage{english}

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\textsuperscript{+} 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-\selectlanguage{greek}κ\selectlanguage{english}B plays a vital role in the regulation of inflammation and immune
response. P65 and P50 are important members of the NF-\selectlanguage{greek}κ\selectlanguage{english}B family, which
binds to their inhibitor protein I\selectlanguage{greek}κ\selectlanguage{english}B 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-I\selectlanguage{greek}κ\selectlanguage{english}B and p-P65 in the lung tissue of mice
in asthma model group was significantly increased, while the expression
of p-I\selectlanguage{greek}κ\selectlanguage{english}B and p-P65 in the lung tissue of mice in asthma model group was
significantly down-regulated by blocking NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway. In addition,
reports have shown that the interaction between CCL21/CCR7 and NF-\selectlanguage{greek}κ\selectlanguage{english}B can
activate I\selectlanguage{greek}κ\selectlanguage{english}B, leading to NF-\selectlanguage{greek}κ\selectlanguage{english}B entry into the nucleus and enhancing its
DNA-binding ability. Stimulation of DCs by CCL21 also leads to the
activation of NF-\selectlanguage{greek}κ\selectlanguage{english}B, 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-\selectlanguage{greek}κ\selectlanguage{english}B 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).

\textbf{CCL21/CCR7 chemokine axis participates in the pathological
process of} \textbf{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).

\textbf{Conclusion and future perspective}

In summary, the specific combination of CCL21 and CCR7 significantly
promotes the activity of immune cells, induces immune cell homing and
promotes immune cell migration and angiogenesis during the process of
immunity and inflammation. The migration of immune cells is a crucial
part of the autoimmune response. Accordingly, the pathological role of
CCL21 and CCR7 has attracted more and more attention from domestic and
foreign scholars in autoimmune diseases (Rizeq et al., 2020)(Figure 5).
With the in-depth exploration of CCL21/CCR7 chemokine axis, it was found
that CCL21 and CCR7 regulate the expression of downstream proteins
through the activation of intracellular signaling pathways to promote
the migration of immune cells to inflammatory and infectious sites,
which participates in the occurrence and development of autoimmune
diseases (McHugh, 2019). Therefore, understanding the signaling
transduction mechanism of CCL21 and CCR7 in autoimmune diseases is
essential for the discovery of potential diagnostic biomarkers and
therapeutic targets, providing a deep foundation and new insights for
the development of new drugs. Therefore, it is of great significance to
elucidate the important role of CCL21/CCR7 chemokine axis in
inflammatory response for reveal the pathological mechanism of
autoimmune diseases and discovering new biomarkers and new drug targets.

\textbf{Acknowledgments}

LH contributed to the drafting and writing the manuscript. DLW
contributed to the drafting. LLZ contributed to the final approval of
the manuscript. This work was financially supported through the National
Natural Science Foundation of China (No. 81673444, U1803129 and
81973332).

\textbf{Conflict of interest}

The authors have declared no conflicts of interest.

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\par\null

\textbf{Figure legends}

\textbf{Figure 1:} The ligand-binding patterns of the
seven-transmembrane domain G-protein-coupled chemokine receptors.

\textbf{Figure 2:} Biological functions of CCL21/CCR7 chemokine axis.

\textbf{Figure 3:} Regulation of CCL21/CCR7 chemokine axis on immune
cells. CCL21/CCR7 chemokine axis has been found to regulate the
functions and activities of immune cells, to balance immune cell
subsets, which could further reduce inflammation and tissue damage in
autoimmune diseases.

\textbf{Figure 4:} Effects of CCL21/CCR7 chemokine axis on MAPKs
signaling pathway, PI3K/AKT signaling pathway and Smads signaling
pathway in autoimmune diseases. MAPKs, PI3K/Akt and Smads signaling
mediated by CCL21/CCR7 chemokine axis participates in the occurrence and
development of autoimmune diseases.

\textbf{F} \textbf{igure 5:} Effect of CCL21/CCR7 chemokine axis on
autoimmune diseases-related indicators. CCL21/CCR7 chemokine axis is
widely involved in the pathological process of autoimmune diseases,
including RA, SS, SLE, PM, AS and so on, through regulating inflammatory
cytokines and disease-related indicators, and mediating signaling
pathways.

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