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), Sjögren 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 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.
Biological characteristics of CCL21/CCR7chemokine axis
Construction, source, distribution and expressionof CCL21/CCR7 chemokine axis
CCL21,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 (Förster 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+CD25+ 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 ɑ-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 ɑ subunit, which forms a free βγ dimer. βγ dimer activates enzymes in two main signaling pathways: phospholipase Cβ2, phospholipase Cβ3 (PLCβ2 and Cβ3) 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+ 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+/CD8+ 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).