CCL20

Official Full Name

C-C motif chemokine ligand 20

Organism

Homo sapiens

GeneID

6364

Background

This antimicrobial gene belongs to the subfamily of small cytokine CC genes. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The protein encoded by this gene displays chemotactic activity for lymphocytes and can repress proliferation of myeloid progenitors. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

Synonyms

CKb4; LARC; ST38; MIP3A; Exodus; MIP-3a; SCYA20; MIP-3-alpha;

Bio Chemical Class

Cytokine: CC chemokine

Protein Sequence

MCCTKSLLLAALMSVLLLHLCGESEAASNFDCCLGYTDRILHPKFIVGFTRQLANEGCDINAIIFHTKKKLSVCANPKQTWVKYIVRLLSKKVKNM

Open

Disease

Psoriatic arthritis

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

CCL20 (C-C Motif Chemokine Ligand 20) is a gene located on human chromosome 2q36.3, encoding a small secreted protein belonging to the CC subfamily of chemokines. The mature protein consists of 70 amino acids, with a molecular weight of approximately 8–10 kDa. It features the characteristic β-chemokine fold stabilized by two disulfide bonds forming a rigid core. Uniquely, CCL20 binds exclusively to the CCR6 receptor, without cross-reactivity to other chemokine receptors. Two alternatively spliced isoforms (isoforms 1 and 2) exist, differing in signal peptide length but sharing identical mature protein structure and activity.

Expression profiling reveals constitutive CCL20 expression in the liver, lung, and lymphoid tissues, and inducible expression in barrier tissues such as the intestine and skin in response to inflammatory stimuli. Its transcription is regulated by NF-κB and AP-1 and can be rapidly upregulated by cytokines such as TNF-α, IL-1β, and IFN-γ, reaching peak levels within two hours. Notably, CCL20 expression exhibits a state-dependent pattern in HBV infection models: upregulated during acute infection (3.43 pg/10μl), but markedly suppressed during chronic infection (1.22 pg/10μl), suggesting that viral immune evasion may involve downregulation of CCL20 to impair immune surveillance.

Biological Functions and Pathogenic Mechanisms

The primary function of CCL20 is to mediate immune cell trafficking via its receptor CCR6. Under physiological conditions, it recruits dendritic cells, regulatory T cells (Tregs), and Th17 cells to mucosal lymphoid tissues, thereby maintaining barrier immune homeostasis. Its C-terminal cationic domain possesses antimicrobial properties, enabling direct killing of pathogens such as E. coli and Staphylococcus aureus, contributing to innate immunity.

In pathological contexts, CCL20 promotes disease progression through three major mechanisms:

Metabolic Liver Disease: In metabolic dysfunction-associated steatohepatitis (MASH), hepatic progenitor cells (HPCs) and cholangiocytes secrete CCL20 under the control of RELB and SOX9 transcription factors. CCL20 activates CCR6 on hepatocytes and triggers the MKK4-JNK-JUN signaling cascade, leading to a 3.5-fold upregulation of oxidized LDL receptor (OLR1), enhanced oxLDL uptake, and cholesterol accumulation, thereby accelerating hepatic fibrosis.
Tumor Microenvironment Remodeling: In breast cancer, tumor-derived CCL20 induces granulocyte-monocyte progenitors (GMPs) to differentiate into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These PMN-MDSCs secrete CXCL2, activating the CXCR2/NOTCH1/HEY1 pathway in tumor cells, enriching cancer stem-like cells and promoting resistance to paclitaxel. In giant cell tumor of bone (GCTB), autocrine CCL20 enhances proliferation and migration of tumor stromal cells (GCTSCs) and induces osteoclast differentiation, leading to osteolytic destruction. Mechanistically, this involves increased AKT phosphorylation and upregulation of the RANKL/c-Fos pathway.
Infection and Immune Dysregulation: During acute HBV infection, CCL20 upregulation may facilitate antiviral T cell recruitment. In contrast, its suppression in chronic infection suggests a role in viral immune evasion by limiting effector cell infiltration.

Figure 1. Overview of CCL20 and other chemokine-mediated mechanisms in the renal cell carcinoma microenvironment, illustrating immune cell recruitment, suppression, and RCC cell EMT activation via the CCL20–CCR6 axis. (Kadomoto S, et al., 2020)

Clinical Significance and Translational Advances

The pathogenic roles of CCL20 make it a promising therapeutic target across various diseases:

MASH Therapy: Preclinical studies demonstrate that CCL20-neutralizing antibodies or CCR6 antagonists can reduce hepatic cholesterol accumulation by over 50%. Combination therapy with thyroid hormone receptor β agonists (e.g., resmetirom) may further enhance therapeutic efficacy.
Oncologic Interventions: In breast cancer models, the CXCR2 antagonist SB225002 combined with docetaxel significantly suppresses tumor growth and overcomes CCL20-mediated chemoresistance. In GCTB patients, serum CCL20 levels correlate with tumor volume, making it a potential non-invasive biomarker for surgical timing.
Anti-infective Strategies: Findings from HBV models suggest that CCL20 agonists could restore immune cell recruitment in chronic infection. However, therapeutic application must carefully balance the risk of exacerbating inflammation.

Challenges and Future Directions

Targeting the CCL20 axis presents several challenges, particularly regarding tissue specificity. While inhibiting CCL20 in the liver may alleviate lipid deposition, doing so in the intestine could impair mucosal immune defenses. Potential solutions include liver-targeted delivery systems such as nanoparticle-encapsulated siRNAs or CCR6 antagonists.

Moreover, the dual immunomodulatory role of the CCL20-CCR6 axis—recruiting both antitumor effector T cells and immunosuppressive Tregs—necessitates precise spatial and temporal regulation. Structure-based design of allosteric modulators that selectively block downstream JNK activation while sparing beneficial STAT3 signaling represents a promising research direction.

Reference

Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci. 2020 Jul 22;21(15):5186.
Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev. 2021 Jul;20(7):102846.
Chen W, Qin Y, Liu S. CCL20 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1231:53-65.

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