CXCL8 - C-X-C motif chemokine ligand 8 | Elisa - Clia - Antibody - Protein

Background

CXCL8, also known as Interleukin-8 (IL-8), is a pro-inflammatory chemokine belonging to the CXC chemokine family. It plays a critical role in immune responses by promoting the recruitment and activation of neutrophils, which are essential in the body’s response to infection and injury. CXCL8 is secreted by a wide range of cells, including macrophages, epithelial cells, endothelial cells, fibroblasts, and keratinocytes, particularly in response to inflammatory stimuli like bacterial products, oxidative stress, and pro-inflammatory cytokines such as IL-1 and TNF-α.

CXCL8 is a potent chemoattractant that directs the migration of neutrophils from the bloodstream to the site of infection or tissue damage. This chemotactic activity is critical for the rapid recruitment of neutrophils, allowing them to carry out their functions in pathogen destruction and the removal of damaged cells.

Due to its prominent role in inflammation, CXCL8 has been associated with various diseases, especially those characterized by chronic inflammation, such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, and cancer.

Protein Structure

CXCL8 is a small 8 kDa protein composed of 72 amino acids in its mature form, though it is initially synthesized as a 99-amino-acid precursor that undergoes proteolytic processing. Structurally, CXCL8 belongs to the CXC chemokine family, where the CXC designation refers to the positioning of two cysteine residues, which are separated by one amino acid in the N-terminal region of the protein.

Key features of the CXCL8 structure include:

• N-terminal domain: This domain is essential for receptor binding and activation. The N-terminal region contains a Glu-Leu-Arg (ELR) motif, which is a critical determinant for CXCL8’s interaction with its receptors and its ability to attract neutrophils. Chemokines with the ELR motif, like CXCL8, tend to be potent neutrophil attractants, whereas CXC chemokines lacking the ELR motif attract lymphocytes instead.
• CXC motif: The CXC motif itself, consisting of two cysteine residues separated by a single amino acid, forms disulfide bonds that stabilize the chemokine’s tertiary structure. These bonds are critical for maintaining the functional conformation of the protein.
• Receptor interaction: CXCL8 functions by binding to two specific G-protein-coupled receptors (GPCRs) on the surface of neutrophils:

1. CXCR1 (IL-8 receptor A): Primarily involved in neutrophil activation and migration.
2. CXCR2 (IL-8 receptor B): Involved in both neutrophil chemotaxis and activation, but also has broader activity, binding to other CXC chemokines.

CXCL8 forms homodimers under physiological conditions, but it can also exist as monomers. The dimeric form appears to have enhanced biological activity in promoting chemotaxis and activating neutrophils. The protein's structure is stabilized by three antiparallel β-strands and a C-terminal α-helix, which help provide stability for receptor interactions.

Classification and Subtypes

CXCL8 is classified as a CXC chemokine based on the structure of its conserved cysteine residues. Within the CXC family, chemokines are further categorized based on the presence or absence of the ELR motif:

• ELR+ CXC chemokines: These chemokines, including CXCL8, contain the Glu-Leu-Arg (ELR) motif near their N-terminal region and are strong inducers of neutrophil chemotaxis.
• ELR- CXC chemokines: These lack the ELR motif and are more involved in the recruitment of lymphocytes rather than neutrophils.

CXCL8 does not have subtypes in the classical sense but exists in multiple truncated forms due to proteolytic processing, which can affect its activity. For example, N-terminal truncations of CXCL8 enhance its affinity for CXCR1 and CXCR2, leading to increased chemotactic potency.

Function and Biological Significance

CXCL8 plays a central role in acute inflammation by regulating the migration and activation of neutrophils. Its primary functions include:

1. Neutrophil Chemotaxis: The most prominent biological activity of CXCL8 is to serve as a chemoattractant for neutrophils, guiding them to sites of infection or tissue injury. Once at the site, neutrophils engulf and destroy pathogens via phagocytosis and release reactive oxygen species (ROS) and proteolytic enzymes that break down damaged tissue.
2. Neutrophil Activation: In addition to recruiting neutrophils, CXCL8 also primes neutrophils for degranulation and respiratory burst, enhancing their bactericidal activity. This activation is crucial for the immune response against bacterial pathogens.
3. Angiogenesis: Besides its role in inflammation, CXCL8 can also promote angiogenesis, the formation of new blood vessels, by stimulating endothelial cells. This function links CXCL8 to tumor progression, as angiogenesis is necessary for supplying growing tumors with oxygen and nutrients.
4. Interaction with Other Cytokines: CXCL8 acts synergistically with other pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 to amplify the inflammatory response. These cytokines can induce the production of CXCL8 in various cells, creating a feedback loop that enhances neutrophil recruitment and activity.
5. Role in Chronic Inflammation: While CXCL8 is beneficial in acute inflammation, its persistent production can lead to chronic inflammatory conditions. In diseases like rheumatoid arthritis and COPD, excessive CXCL8 production results in prolonged neutrophil activation and tissue destruction, contributing to disease pathology.

Clinical Issues

Due to its pivotal role in inflammation, CXCL8 has been implicated in various inflammatory and immune-mediated diseases. High levels of CXCL8 have been associated with the following clinical conditions:

1. Chronic Obstructive Pulmonary Disease (COPD): CXCL8 is overexpressed in the lungs of COPD patients, where it drives neutrophil recruitment and activation, leading to chronic inflammation and tissue damage in the airways. This results in impaired lung function and contributes to disease progression.
2. Rheumatoid Arthritis (RA): In RA, excessive CXCL8 production in the synovial tissue leads to an influx of neutrophils into the joints, resulting in chronic inflammation, joint destruction, and pain.
3. Cancer: CXCL8 plays a dual role in cancer progression. Its ability to promote angiogenesis supports tumor growth and metastasis. Additionally, CXCL8 can modulate the tumor microenvironment, enhancing immune evasion by recruiting immune-suppressive cells such as neutrophils that support tumor survival.
4. Asthma: CXCL8 contributes to airway inflammation in asthma by attracting neutrophils and promoting mucus secretion, leading to airway obstruction and worsening of symptoms in severe cases.
5. Infectious Diseases: CXCL8 is involved in the immune response to bacterial infections, such as sepsis, where its dysregulated production can lead to overwhelming inflammation and tissue damage. In sepsis, elevated levels of CXCL8 have been correlated with poor outcomes due to excessive neutrophil activation and tissue injury.
6. Autoimmune Diseases: CXCL8 has also been implicated in several autoimmune diseases, including inflammatory bowel disease (IBD) and psoriasis, where its overexpression leads to excessive neutrophil recruitment and tissue damage.

Summary

CXCL8, also known as Interleukin-8 (IL-8), is a potent pro-inflammatory chemokine that plays a key role in neutrophil recruitment and activation during immune responses to infection and tissue damage. Structurally, it is a small protein with an ELR motif that enables it to bind to its receptors, CXCR1 and CXCR2, on neutrophils, facilitating their migration to sites of inflammation. CXCL8 also promotes angiogenesis, contributing to tumor progression and metastasis.

Clinically, CXCL8 is implicated in various inflammatory diseases such as COPD, rheumatoid arthritis, and asthma, as well as in cancer progression. It is a central mediator in both acute and chronic inflammation, and its dysregulation can lead to excessive neutrophil activity, resulting in tissue damage and disease exacerbation. Therapeutic strategies targeting CXCL8 and its receptors are being explored to mitigate its harmful effects in diseases characterized by chronic inflammation and neutrophil-driven pathology.

Understanding the biology of CXCL8 and its interactions with immune cells is critical for developing new treatments for inflammation-related diseases and improving clinical outcomes in conditions where excessive neutrophil activity contributes to disease severity.