CHEMOKINES: CHEMOTACTIC FACTORS WHICH PLAY A ROLE IN INFECTION AND INFLAMMATION

Frydas I, Castellani ML. Chemokines: Chemotactic factors which play a role in infection and inflammation. International Journal of Infection. 2023;7(1):1-6.

I. Frydas^1* and M.L. Castellani²

¹ Department of Parasitology, Aristotle University, Thessaloniki, Greece;
² Immunology Division, University “G. D’Annunzio” of Chieti-Pescara, Chieti, Italy.

*Correspondence to:
Dr. Ilias Frydas,
Department of Parasitology,
Aristotle University,
54124 Thessaloniki, Greece.
e-mail: ilias.frydas@gmail.com

Received: 04 November, 2022 Accepted: 13 March, 2023

ISSN 1972-6945 [online] Copyright 2023 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Chemokines are potent inflammatory mediators that participate in the immune response in infections caused by microorganisms. Parasitic or microbial infections, injuries, tumors, and autoimmune diseases alter homeostasis and induce inflammation. In the infectious state, immune cells are activated and release chemical mediators such as cytokines and chemokines. Chemokines are divided into CXC, CC, and CX3C families, depending on the arrangement of their first two cysteine molecules, and mediate their effects by binding to chemokine receptors, which are G protein-coupled receptors expressed on the surface of immune cells. Chemokines bind receptors to attract specific immune cells to the site of infection. For instance, CXC chemokines primarily attract neutrophils, while CC chemokines tend to attract monocytes, lymphocytes, and eosinophils. After an infection, macrophages and tissue cells play a primary role in the production and mobilization of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Chemokines induce cellular changes during infections such as increased adhesion of immune cells to blood vessel walls, migration to the site of infection, and activation of antimicrobial functions. Studies on mice infected with protozoa and metazoa have shown that chemokines of the CC and CXC families actively participate in the immune response. For example, in leishmaniasis, the CC chemokine MCP-1, together with other chemokines, exerts a chemotactic action on specific leukocytes, increasing resistance to the parasite.

KEYWORDS: Chemokine, chemotactic, infection, inflammation, immunity

INTRODUCTION

The inflammatory reaction is the body’s response to a multitude of factors that directly or indirectly disturb its homeostasis (1). These factors can be infections (parasitic or microbial), injuries, tumors, or autoimmune diseases (2). The inflammatory reaction can be acute or chronic, depending on the duration of inflammation and the leukocyte mechanisms that are involved.

Inflammation is a crucial biological response of the body’s immune system to harmful stimuli such as pathogens, damaged cells, or irritants. It is a protective mechanism aimed at removing these harmful stimuli and initiating the healing process. While acute inflammation is beneficial and necessary for healing, chronic inflammation can lead to various diseases and conditions, including autoimmune disorders, cardiovascular diseases, and cancer (3).

Inflammation and infection are often interrelated, although they are not synonymous. Infection refers to the invasion and multiplication of microorganisms such as bacteria, viruses, fungi, and parasites, that are not normally present within the body. The body’s immune response to infection typically involves inflammation, which helps to contain and eliminate the invading pathogens (4).

When an infection occurs, the immune system is activated to fight off the invading microorganisms. This activation results in the release of various inflammatory mediators, including cytokines and chemokines, which coordinate the immune response (5). The signs of inflammation- redness, heat, swelling, pain, and loss of function- are the result of increased blood flow, immune cell infiltration, and fluid accumulation in the affected tissue.

Chemokines are a subset of cytokines, which are small proteins secreted by cells that have a specific role in immune responses, where they function primarily as chemoattractants to attract immune cells to the site of infection or injury. Chemokines bind to specific receptors on the surface of target cells, guiding them to the site where they are needed.

There are three main subfamilies of chemokines which are classified based on their structure and the arrangement of their cysteine residues: CXC, CC, and CX3C (6).  Each subfamily has distinct functions and targets different types of immune cells. For instance, CXC chemokines primarily attract neutrophils, while CC chemokines tend to attract monocytes, lymphocytes, and eosinophils (7).

DISCUSSION

In the recent past, the use of specific monoclonal antibodies which recognize binding to certain leukocytes and the identification of factors involved in leukocyte migration, have significantly helped in understanding the mechanisms of cooperation between endothelial cells and leukocytes (8).

Many chemical substances mediate inflammation, such as biologically active lipids that produce large and small peptides, although most of them lack specificity for the stimulation of leukocyte populations. In the mid-1980s, experimental research led to the discovery of chemotactic cytokines and chemokines, which are responsible for the concentration and extra-vascularization of specific populations of leukocytes (9). The production of these chemokines by local tissue cells (macrophages, epithelial, endothelial, fibroblasts, liver, keratinocytes) mainly relies on the cytokine network. Tissue macrophages can fully support and control the inflammatory reaction by releasing increased amounts of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF), which results in the stimulation of neighboring immune cells, including mast cells, and the production of chemokines by the corresponding cells (10).

Chemokines with a molecular weight between 8-10 Kd are separated into two distinct families of supergenes, CXC and CC, depending on the arrangement of the first two cysteine molecules they have. More specifically, the CXC family has two separated cysteine molecules, while in the CC family, the arrangement of the two cysteine molecules is adjacent (11).

The genes of the CXC chemokines are located on human chromosome 4 and show 20-25% similar structure. So far, research has led to the identification of various chemokines in this family (12) (Table I).

Table I. Various chemokines that are part of the CXC family.

IL-8 is the chemokine of the CXC family that has been the most extensively studied. A multitude of cells are responsible for its production, including monocytes, phagocytes, keratinocytes, epithelial cells, hepatocytes, and fibroblasts (13). IL-8 is a chemotactic factor mainly for neutrophils and in its structure, there is an absence of the three amino acid residues Glu, Leu, and Arg. IL-8 binds to the neutrophil receptor and, to a lesser extent, to basophils and eosinophils. The chemokines IP-10, MIG, and PRF-4 do not carry the three amino acids (Glu-Leu-Arg) and have limited abilities to activate neutrophils (14).

The CC chemokine family is related to the CXC family, with genes located on human chromosome 17q.11.2. (15). Members of the CC family include macrophage inflammatory protein-1 alpha, beta (MIP-1a,b), monocyte chemoattractant protein 1, 2 and 3 (MCP-1, 2, 3), and regulated upon activation, normal T expressed and presumably secreted (RANTES) (16). The chemokines of this family specifically activate and mobilize monocytes and/or macrophages, some types of lymphocytes, basophils, eosinophils, as well as other cells, but not neutrophils. Also, they participate in the initial manifestation and the regulatory mechanisms throughout the duration of the delayed-type reaction hypersensitivity (17).

RANTES is an interesting 8-10 Kd protein that is produced by macrophages and endothelial cells and is chemotactic for monocytes, eosinophils, CD4 lymphocytes, and memory T lymphocytes (CD4 5Ro+). It also activates and degranulates eosinophils and basophils (18).

Another protein of interest, MCP-1, has the same efficacy as the complement protein C5a in allergies. It is produced by endothelial and smooth muscle cells as well as fibroblasts after their stimulation with IL-1 and TNF (19).  Although it has less ability to stimulate eosinophils compared to other chemokines, it nevertheless activates the binding molecules of integrins, and activates and attracts monocytes, basophils, and mast cells, which release high amounts of histamine and leukotrienes without the involvement of IL-3.

In addition, the chemokine MIP-1a seems to have less chemotaxis abilities when compared to RANTES and MCP-1 (20). It is produced by macrophages, T and B leukocytes, mast cells, and fibrils. It activates and attracts monocytes and macrophages, as well as T-lymphocytes (CD8 and CD4), and degranulates basophils with the cooperation of interleukin-3 (IL-3).

Certain differences between the chemokines of the two families regarding their ability to bind to basophils and eosinophils are probably due to the expression of specific receptors on the surface of these cells, which bind selectively to chemokines of the CC family, or to the existence of low- or high-affinity binding receptors (21).

Chemokines mediate their effects by binding chemokine receptors, which are G protein-coupled receptors expressed on the surface of immune cells (22). This binding triggers a cascade of intracellular signaling events that lead to changes in cell behavior, such as increased adhesion to blood vessel walls, migration towards the infection site, and activation of antimicrobial functions (Fig.1).

 Fig. 1. Chemokines bind their G protein-coupled receptors on the cell membrane, which initiates a cascade of intracellular signaling events including the activation of JNK3, p65, and subsequently, NF-kB which then translocates into the nucleus and mediates immune regulation.

The regulation of chemokine expression and activity is tightly controlled, as excessive or inappropriate chemokine production can contribute to chronic inflammation and tissue damage. For example, in autoimmune diseases like rheumatoid arthritis, elevated levels of certain chemokines can lead to persistent inflammation and joint destruction (23).

Understanding the roles of chemokines in inflammation and infection has significant clinical implications. Therapeutic strategies targeting chemokines and their receptors are being explored for treating various inflammatory and autoimmune diseases (24). By modulating chemokine activity, it may be possible to reduce harmful inflammation while preserving the body’s ability to fight infections.

In summary, inflammation is a vital immune response to infection and injury, with chemokines playing a central role in directing immune cells to affected areas. While essential for host defense and healing, the regulation of inflammation and chemokine activity is crucial to prevent chronic inflammatory diseases and maintain overall health (25).

After an infection, macrophages and tissue cells play a primary role in the production and mobilization of pro-inflammatory cytokines such as IL-1, IL-6, and TNF. These cytokines, which are only part of the cytokine network, have the goal of locating the inflammation, limiting the inflammatory reaction, and activating the tissue cells in the inflamed area to produce additional mediators which maintain the immune response (26).

The host response to the pathogen is a concerted effort of various mechanisms intended to stimulate and direct leukocytes to the area of the immune response (Table II). This mobilization of immune cells can aid healing by destroying pathogens, reactivating the tissue, and at the same time, suppressing immune response mechanisms such as the production of cytokines, the expression of binding molecules, and the activation of cells (27).

Table II. Important mechanisms of the host immune response to direct leukocytes to the infection site.

In the case of pathogen resistance, suppression mechanisms, and damage maintenance (chronic inflammation), the organism is reactivated in order to express new binding molecules to secrete more cytokines and activate a larger number of cells (28).

In laboratory animals with allergic lung inflammation, it has been seen that the expression of the chemokines MIP-1a and MCP-1, 2, and 3 caused mononuclear cells and eosinophils to concentrate in the bronchi (29).

Regarding experimental parasitic infections caused by protozoa and metazoa, recent in vivo and in vitro studies in mice have shown that chemokines of both the CC and CXC families participate in the immune response. More specifically, MCP-1 exerts a chemotactic action that causes the infiltration of leukocytes in certain parasitosis, such as leishmaniasis (30). Together with RANTES, MIP-1a, and MIP-2b, MCP-1 controls the intracellular multiplication of the parasite Trypanosoma cruzi and could enhance resistance to it (31).

In addition, the chemokine MCP-1 was seen to increase the concentration of lymphocytes at the sight of infection with the nematode parasite Trichinella spiralis, showing its importance in the inflammatory response (32). In another experiment with mice that were infected with the cestode parasite Echinococcus granulosus, the chemokines MCP-1 and, to a lesser extent, MIP-2 were shown to actively participate in the immune response (33).

CONCLUSIONS

Chemokines are mediators of inflammation which act selectively on specific cell populations, regulate specific cellular functions, and actively participate in all phases of the inflammatory reaction. There have already been relevant clinical trials with encouraging results for diseases such as bronchial asthma, chronic inflammatory bowel disease, atherosclerosis, and allergic dermatitis in humans. In the future, more experimental research should be carried out to further clarify the mechanisms of action of chemokines.

Efforts to study chemokines should be focused on in vitro and in vivo experimental studies to understand their exact role in infection and inflammation. The cooperation of cytokines and chemokines could expand the immune response and modulate inflammation, since the severity of inflammation depends on the levels of cytokines that promote or inhibit it.

Understanding the mechanisms of chemokines and the special properties of each one separately will help in the research related to their clinical application, since their increase or decrease in blood, tissues, or other biological materials can be an indicator of the course of the disease.

Conflict of interest

The authors declare that they have no conflict of interest.

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