The virtue lies in moderation: chemokines stories

---

Why moderation is a virtue for our body?

Ancient Romans used to say in Latin "In medio stat virtus" (which can be translated as "the virtue lies in moderation"). They meant that an extreme life (either full of excesses of with constant lack of anything) is not the wisest way of living and the "good" alternative to follow would be a moderate life style. What if this idea came to them by observing the nature around them? Nature works according to a similar principle, since it does not like waste of energy and resources. This is the reason why our body reacts in specific ways whenever an unbalanced condition is happening (naturally, genetically, or artificially), in order to re-establish the equilibrium.

Many functions in our body are regulated by specific biological molecules., called proteins. Proteins are produced (or expressed, as biologists say) as a result of a specific DNA data set. It is just the DNA that decides if and what proteins our body is going to have. This process starts already during the embryonal stage (when we are little like a bean!) and it is finely regulated and controlled to avoid mistakes as much as possible. Since our body functioning is highly complicated from an evolutionary point of view, several types of proteins have been discovered and studied to understand their roles, especially for therapeutic purposes.

A diverse family of proteins: chemokines receptors and CXCR4

Among the several proteins that can be found in our body, some are defined "receptors", because of their ability to bind molecules called "ligands", which can activate or inhibit the activity of the specific receptors that they are bound to. Different types of receptors exist in nature with diverse (but specific) functions. An example is represented by chemokine receptors, which take their names from their ability to bind chemokines to be activated/inhibited. These chemokines are small secreted proteins, which play a key role in important biological processes, such as the development and the homeostasis of the immune system, and are involved in every type of immune and inflammatory responses.

The chemokine receptors are a typical example of proteins whose expression needs to be "balanced" in our body and this expression can change upon different stimuli when required. For example, in physiological conditions, the chemokine receptor CXCR4 is expressed in the body to control, by interacting with its ligand CXCL12, several key processes of the embryonal development, such as development of the hematopoietic, cardiovascular, and nervous system and it has an important role also in controlling the leukocytes movement in case of inflammation.

CXCR4 has been showed to be correlated to several types of cancer. In some of them, CXCR4 is overexpressed (so it is produced in excess compared to physiological levels), in others this receptor is down-expressed (so levels of CXCR4 are decreased). A well known example of this phenomenon is represented by the breast cancer. Indeed, CXCR4 levels are increased in presence of breast cancer when is solid tumour state. However, this changes when breast cancer reaches the metastatic stage of its progression, where instead the levels of CXCR4 detected are decreased compared to orthotopic tumours (orthotopic: something that occurs in the normal or usual place in the body).

What can cause changes in chemokine receptors expression?

Changes in the levels of chemokine receptors can be connected to several factors, the most common of which is a genetic mutation in the gene that codifies (in other words, contains the information for) the expression of the receptor of interest. An example in this case can be CCR5. This is well known because of its role as a co-receptor to allow the entry of HIV-1 virus in host cells. When this receptor is overexpressed, this leads to an increased susceptibility to being infected by HIV-1, because CCR5 relocate to the membrane of the host cells and binds a protein, called gp120, present on the outer side of HIV-1 particles.

Instead, the genetic mutation of CCR5 called CCR5-Δ32 deletion (therefore, a 32 amino acids long region of CCR5 is deleted) shows the beneficial effect of preventing the production of a functional CCR5 protein on the cell surface. This, as a result, leads to an increased resistance to HIV-1 infection because the virus cannot bind to and enter the cells.

Take-home message

• Nature tends to balance each function in our body to avoid waste.

• Genetic mutations can happen and lead to over- or down-expression of proteins involved in controlling physiological processes in our body.

• In some cases, the same protein can be over- or down-expressed with different effects (usually pathological, but not always!)

• It is important to understand better which proteins and which mutations lead to specific pathological conditions to find new and more efficient therapeutic strategies to treat these diseases.

  
  

References

Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944-2971. doi:10.1111/febs.14466

Jacobson O, Weiss ID. CXCR4 chemokine receptor overview: biology, pathology and applications in imaging and therapy. Theranostics. 2013;3(1):1-2. doi:10.7150/thno.5760

Zhao H, Guo L, Zhao H, Zhao J, Weng H, Zhao B. CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget. 2015;6(7):5022-5040. doi:10.18632/oncotarget.3217

Nobutani K, Shimono Y, Mizutani K, et al. Downregulation of CXCR4 in Metastasized Breast Cancer Cells and Implication in Their Dormancy. PLoS One. 2015;10(6):e0130032. Published 2015 Jun 17.

doi:10.1371/journal.pone.0130032

Lopalco L. CCR5: From Natural Resistance to a New Anti-HIV Strategy. Viruses. 2010;2(2):574-600. doi:10.3390/v2020574

Cuesta-Llavona E, Gómez J, Albaiceta GM, et al. Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity. Int Immunopharmacol. 2021;98:107825. doi:10.1016/j.intimp.2021.107825

Assessed and Endorsed by the MedReport Medical Review Board