Chemokines are a family of small signaling proteins that act as chemical attractants, guiding the movement of various cells throughout the body. Among these molecules is Chemokine (C-X-C motif) ligand 14, commonly abbreviated as CXCL14. This particular chemokine stands out due to its unique characteristics, including its consistent presence in healthy tissues, unlike many other chemokines that appear primarily during injury or infection. CXCL14, also known by its earlier name BRAK, meaning breast and kidney-expressed chemokine, plays diverse roles in biological processes.
Function in the Immune System
CXCL14 exhibits a distinct behavior within the immune system, primarily through its constitutive expression in various healthy tissues. Unlike many other chemokines that are only produced when the body faces an injury or infection, CXCL14 is consistently present in tissues such as the skin, breast, kidney, brain, muscles, and lungs under normal conditions. It is thought that fibroblasts are a primary source of this chemokine in normal tissues.
This chemokine plays a role in guiding specific immune cells, including monocytes, immature dendritic cells, and natural killer (NK) cells. For example, it can attract monocytes and activate them, especially in the presence of inflammatory mediators like prostaglandin-E2. Its ability to stimulate the migration of activated NK cells and immature dendritic cells suggests a function in routine immune surveillance.
Influence on Metabolism
CXCL14 also plays a part in regulating the body’s metabolic processes, particularly concerning glucose homeostasis and insulin sensitivity. This chemokine is found in significant amounts within adipose (fat) tissue, as well as the liver. Its expression and secretion in adipose tissue can increase with insulin administration and a high-fat diet, linking it to conditions like obesity.
Research in mice has revealed a complex relationship, with some studies indicating that elevated CXCL14 in white adipose tissue, especially in obese mice fed a high-fat diet, may contribute to insulin resistance. This effect might be related to its role in recruiting macrophages to fat tissue, which can lead to chronic inflammation. Conversely, other studies suggest that CXCL14 can enhance insulin-dependent glucose uptake in adipocytes and improve overall glucose homeostasis.
The Dual Role in Cancer
CXCL14 has a complex role in cancer development and progression, acting as both a suppressor and, in some contexts, a promoter of tumor growth. In many types of cancer, CXCL14 is significantly downregulated or even absent in malignant cells compared to healthy tissues. This makes it a tumor-suppressive factor in several cancers, including head and neck, lung, liver, and some colorectal cancers.
Its tumor-suppressive actions are linked to its capacity to recruit anti-tumor immune cells into the tumor microenvironment. CXCL14 can attract natural killer (NK) cells, T cells, and macrophages. It also plays a role in inhibiting angiogenesis and can directly suppress the motility and migration of tumor cells. Restoring CXCL14 expression in certain cancer cells has been shown to inhibit tumor growth in experimental models, suggesting its potential as an immunotherapeutic agent.
However, the influence of CXCL14 in cancer is highly dependent on the specific cancer type and its surrounding cellular environment. In some malignancies, such as certain breast and prostate cancers, high CXCL14 expression has been correlated with increased invasiveness or poor patient survival. This pro-tumor effect might stem from its contribution to chronic inflammation within the tumor microenvironment or its ability to modulate the function of regulatory T cells, which can suppress anti-tumor immune responses.
The Receptor Puzzle
Most chemokines exert their effects by binding to specific receptors located on the surface of target cells. This binding initiates a cascade of signals inside the cell, leading to various cellular responses. However, CXCL14 presents a scientific mystery: despite extensive research, no specific, high-affinity receptor for CXCL14 has been definitively identified. This absence has led scientists to label CXCL14 an “orphan chemokine,” meaning its primary signaling partner remains unknown.
The lack of an identified conventional receptor has prompted various theories about how CXCL14 might exert its diverse biological effects. Some researchers propose that it might interact with known chemokine receptors. Another possibility is that CXCL14 engages a novel, as-yet-undiscovered signaling pathway or an atypical receptor outside the typical chemokine receptor family. While some studies have suggested candidates like MRGPRX2, contradictions exist, particularly regarding its expression on immune cells and its conservation across species.