Introduction
Chemokines are a large family of small cytokines with low molecular weights ranging from 7 to 15 kDa, which play crucial roles in immune responses by directing the migration and residence of immune cells. When the body is stimulated by an antigen, chemokines are secreted by various cells, including endothelial and dendritic cells (DCs). Chemokines are categorized into four subfamilies based on the position of two cysteines at the N-terminus: C, CC, CXC, and CX3C. They are also classified into homeostatic and inflammatory chemokines based on their expression patterns and functions within the immune system. Chemokine receptors, which belong to the G-protein-coupled receptor family, mediate the effects of chemokines by facilitating the migration of immune cells to sites of inflammation or injury.
Related Products
Among the chemokines, C-C chemokine ligand 25 (CCL25) and its receptor, C-C chemokine receptor 9 (CCR9), have garnered significant attention due to their roles in regulating inflammation and the progression of various diseases. CCL25 is primarily expressed in the thymus and intestinal epithelium, playing a key role in T-cell development and migration. CCR9 is expressed on various immune cells, including dendritic cells, neutrophils, lymphocytes, monocytes, macrophages, and vascular endothelial cells. The interaction between CCR9 and CCL25 has been implicated in several inflammatory diseases, making them potential therapeutic targets.
Fig. 1 Schematic diagram illustrating the regulation of molecular mechanisms of CCR9/CCL25 in inflammatory diseases (Wu X., et al. 2021).
CCR9 and CCL25 Expression in Tissue
In 1997, researchers first isolated CCL25 cDNA from the thymus of recombinase activation gene-1 (RAG-1) deficient mice, designating it as thymus-expressed chemokine (TECK). They found that CCL25 has weak sequence homology with other members of the CC chemokine family and is located on mouse chromosome 8. Besides the thymus, CCL25 mRNA is detected at substantial levels in the small intestine and at low levels in the liver. CCL25 is highly expressed in the small intestinal epithelium and thymus, where it regulates the trafficking of gut-specific memory/effector T cells via the upregulation of integrin homing receptor α4β7 and CCR9.
CCR9 expression is limited to specific subsets of immune cells in circulating white blood cells, including activated B cells, CD4 and CD8 T cells, and plasmacytoid dendritic cells in mice. In peripheral tissues, CCR9+ cells are predominantly found in the colon, thymus, and small intestine. The expression of CCR9 on intraepithelial lymphocytes, mainly CD8+ cells, further emphasizes its role in mucosal immunity.
The Role of CCR9/CCL25 in Inflammatory Diseases
Cardiovascular Disease
Cardiovascular diseases (CVD), including myocardial infarction (MI), heart failure, and cardiac hypertrophy, are chronic vascular inflammatory diseases with high morbidity and mortality rates. Studies on CCR9 knockout mice have demonstrated that the absence of CCR9 improves survival rates, reduces infarct size, and enhances cardiac function after MI by attenuating cardiomyocyte apoptosis and suppressing pro-inflammatory cytokine expression. Additionally, CCR9 is involved in structural remodeling of the heart by interfering with NF-κB and MAPK signaling pathways.
In heart failure, CCR9 expression is significantly increased in failing human hearts and animal models of cardiomyocyte hypertrophy. The loss of CCR9 in mice reduces hypertrophy caused by pressure overload, decreases heart size, and alleviates interstitial fibrosis by modulating the protein kinase B mammalian target of the rapamycin GSK-3β signaling cascade. These findings suggest that CCR9 could serve as a novel therapeutic target for myocardial hypertrophy and heart failure.
Hepatitis
Hepatitis involves liver inflammation caused by various factors, including parasites, viruses, drugs, bacteria, and autoimmune reactions. Inflammatory macrophages play a crucial role in liver injury and fibrosis. CCR9+ inflammatory macrophages have been shown to exacerbate liver damage through the production of inflammatory cytokines and the promotion of Th1 cell development during acute liver injury. Studies using CCR9 knockout models have confirmed that these macrophages originate from bone marrow-derived monocytes and contribute to liver fibrosis and hepatocellular damage.
In primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease, the expression of CCL25 is increased in the liver, correlating with hepatic inflammation and the recruitment of CCR9+ T cells. This suggests that the CCR9/CCL25 axis could be a potential therapeutic target for liver diseases, including PSC and other forms of hepatitis.
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the accumulation of macrophages, T cells, and B cells in the synovium, leading to joint destruction and pain. CCR9 and CCL25 are expressed at higher levels in RA synovial tissues compared to osteoarthritis tissues. The interaction between CCR9 and CCL25 promotes cell infiltration and the production of inflammatory mediators, such as IL-6 and MMP-3, in RA synovial tissues.
Blocking CCR9 or CCL25 has been shown to reduce the migration of inflammatory cells to synovial tissues and suppress collagen-induced arthritis in mouse models. These findings highlight the potential of CCR9/CCL25 as therapeutic targets for RA.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) encompasses chronic inflammatory conditions, including ulcerative colitis (UC) and Crohn's disease (CD). Both diseases involve abnormal immune responses in the gastrointestinal tract. Studies have shown that CCR9 and CCL25 are upregulated in the large intestine during colitis, and their absence exacerbates colitis by increasing the accumulation of activated macrophages and pro-inflammatory cytokines.
The CCR9 antagonist CCX282-B (vercirnon) reached phase III clinical trials for the treatment of CD but was terminated due to poor efficacy. Despite this setback, the role of CCR9/CCL25 in regulating intestinal inflammation suggests potential for future therapeutic strategies targeting these molecules in IBD.
Asthma
Asthma is characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to stimuli. Chemokine receptors, including CCR9, are involved in leukocyte recruitment and play a role in asthma pathology. In mouse models of allergic inflammation, the absence of CCR9 reduced airway inflammation and hyperresponsiveness, indicating that CCR9/CCL25 could be therapeutic targets for asthma.
Conclusion
Chemokines and their receptors, particularly the CCR9/CCL25 axis, play critical roles in the regulation of immune responses and the development of various inflammatory diseases. The expression of CCR9 and CCL25 in specific tissues and their involvement in inflammatory processes highlight their potential as therapeutic targets. Studies on cardiovascular disease, hepatitis, rheumatoid arthritis, inflammatory bowel disease, and asthma have demonstrated the significant impact of CCR9/CCL25 in modulating inflammation and disease progression.
Further research is needed to fully elucidate the mechanisms by which CCR9/CCL25 contributes to these diseases and to develop targeted therapies that can effectively modulate their activity. The ongoing investigation into the roles of CCR9 and CCL25 will undoubtedly advance our understanding of inflammatory diseases and pave the way for novel therapeutic approaches.
References
- Wu X., et al. The roles of CCR9/CCL25 in inflammation and inflammation-associated diseases. Frontiers in Cell and Developmental Biology. 2021, 9: 686548.
- Trivedi P. J., et al. Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity. Journal of Autoimmunity. 2016, 68: 98-104.
.
