Chemokines are a class of molecular signaling molecules that play an important role in guiding and regulating the movement and migration of immune cells, inflammatory cells and other cells in the body. Chemokines are usually produced by damaged tissues, inflammatory cells, or immune cells. By binding to specific receptors, they trigger intracellular signal transduction pathways, leading to directional movement and chemotactic responses of cells.
Chemokines can be divided into several families, including CXC Chemokine Family, CC Chemokine Family, CXCL16 Chemokine Family, XC Chemokine Family and so on. These chemokines play important biological functions in inflammation, immune response, tissue repair and development.
The main function of chemokines is to guide immune cells and inflammatory cells to move to the lesion or infection area, so as to participate in the occurrence and regulation of inflammatory response. They can affect the extent and duration of inflammatory responses by regulating leukocyte adhesion, migration, and infiltration. Chemokines can also affect the activation, differentiation and function of immune cells, and participate in the regulation and regulation of immune responses.
During the disease process, abnormal expression or dysfunction of chemokines may lead to excessive or insufficient inflammatory response, which is associated with various inflammatory diseases, autoimmune diseases, tumor metastasis and infection. Therefore, chemokines and their receptors have become important targets for research and treatment of inflammatory diseases.
Chemokines & Receptors
Understanding Chemokines and Their Role in the Immune System
Directed Migration of Immune Cells: A Vital Component of Immune Response
Directed migration of immune cells is crucial for the initiation and completion of a collective immune response. Chemokines, a type of cytokines, play a pivotal role in controlling the directional migration of cells. This function is mediated through interactions with chemokine receptors. By facilitating the movement of various immune cells within the circulatory system, between tissues and organs, chemokines enable them to reach sites of infection, trauma, abnormal proliferation, and perform essential functions like clearing infections, promoting wound healing, and eliminating abnormal cells. Consequently, the chemokine system is vital for maintaining tissue cell balance and serves as a key player in numerous aspects of immune system function, including pathogen clearance, inflammatory response, pathogen infection, cell and organ development, wound repair, tumor formation and metastasis, as well as transplant immune rejection. Controlling and modulating the chemokine system's function by targeting chemokines and their receptors through signal transduction activation or antagonism holds promising prospects for controlling and treating related diseases.
Chemokines: Small Molecule Secreted Proteins Guiding Cellular Migration
Chemokines are small molecule secreted proteins consisting of 70 to 100 amino acids that enable chemotactic cell migration. They constitute the largest family of cytokines, with over 40 types identified in humans thus far. When stimulated by growth factors, interferons, viral products, bacterial products, or other stimuli, fibroblasts, endothelial cells, epidermal cells, and immune cells can secrete different chemokines. The molecular structure of chemokines contains four conserved cysteines (C). Depending on whether additional amino acids are inserted between the first two C's near the amino terminus (N-terminus) of the molecule, they are categorized into four subclasses: CXC class (with the insertion of 1 amino acid residue), also known as class A chemokines; CC class (without the insertion of other amino acid residues), also known as class B chemokines; CX3C class (with the insertion of 3 other amino acids), and class C (with only 1 C at the N-terminus). The chemokines discovered so far primarily belong to class A and class B. Structurally, they fold into a secondary structure characterized by a free N-terminus, three reversely folded B-sheets, and the carboxy-terminus (C-terminus) of the A helix through disulfide bonds.
Understanding Chemokine Receptors and Their Role in Cellular Function
Chemokine Receptors: GPCR Mediators of Chemokine Function
Chemokine receptors are a class of transmembrane receptors known as GTP-protein-coupled receptors (GPCRs). These receptors play a crucial role in mediating the functions of chemokines and are typically found on the cell membranes of immune cells and endothelial cells. The molecule itself consists of approximately 330 amino acids and is divided into seven transmembrane regions. These regions create distinct sections within the receptor, including the free extracellular N-terminus, three extracellular loops, three intracellular loops, and the C-terminal portion. The second loop within the cell acts as the binding site for heterotrimeric G-proteins and contains a characteristic amino acid sequence known as the aspartic acid-arginine-tyrosine box (DRY box). The A subunit of the heterotrimeric G-protein coupled with chemokine receptors is GiPo, which is sensitive to pertussis toxin. Based on the classification of chemokines, receptors that bind to CC chemokines are referred to as CC receptors (CCR), receptors that bind to CXC chemokines are known as CXC receptors (CXCR), and receptors that bind to C and CX3C chemokines are categorized as C and CX3C receptors.
Key Roles and Structure of Chemokine Receptors
Studies have shown that deletion mutants of the N-terminal amino acid residues of chemokines are unable to bind to their receptors. This confirms the crucial role of N-terminal sequences in the binding of chemokines to receptors and subsequent signal transduction. The C-terminal region greatly enhances the signal transduction function of the N-terminal peptide. The 1st-beta-sheet structure has the ability to bind to aminodextran GAG on vascular endothelial cells, allowing for attachment and enrichment on these cells. The N-terminus and multiple extracellular loops of chemokine receptors participate in ligand binding, with the N-terminus sequence largely determining the specific selectivity of receptors for chemokines. The C-terminal region, which is the intracellular part of chemokine receptors, often consists of serine and threonine residues. Phosphorylation of these residues may be involved in signal transduction and receptor internalization following activation.
Interactions and Regulation of Chemokine Systems
In ligand-receptor binding experiments, it has been observed that there is redundancy in the binding between chemokines and receptors. This means that one chemokine can bind to several chemokine receptors, and vice versa. This redundancy allows for fine regulation of chemokine systems in vivo. In vitro chemotaxis experiments have demonstrated that a single chemokine can attract immune cells expressing different chemokine receptors, and likewise, a single immune cell can be attracted by multiple chemokines. This redundancy in the interaction of chemokines and their receptors enables precise regulation of immune cell migration and interactions. In vivo, the expression and distribution of various chemokines in different tissues and at different times, along with the expression and distribution of chemokine receptors in different immune cell populations, determine the specificity of chemokine-receptor interactions and play a crucial role in directing immune cell migration and interaction.
Understanding the Chemokine Signaling Pathway: Regulation of Cell Movement and Chemotaxis
The Chemokine Signaling Pathway: A Molecular Cascade Controlling Cell Responses
The chemokine signaling pathway encompasses a series of molecular events that occur after the binding of chemokines to their respective cell surface receptors. This pathway plays a vital role in regulating cell movement, migration, and directional responses, serving as a fundamental mechanism for chemokine-mediated cell chemotaxis.
A Summary of the Chemokine Signaling Pathway
The chemokine signaling pathway can be summarized in the following steps:
- Receptor Activation: Chemokines bind to chemokine receptors located on the cell surface, initiating receptor activation. Chemokine receptors typically belong to the class of G protein-coupled receptors (GPCRs) and consist of seven membrane domains.
- G Protein Activation: Once the receptor is activated, the associated G protein is also activated. This activation triggers the release of GDP (guanosine diphosphate) from its resting state and facilitates the binding of GTP (guanosine triphosphate), allowing the G protein to enter an active state.
- Secondary Signal Transduction: The activated G protein interacts with effector proteins (such as adenylyl cyclase, phosphatidylinositolase, etc.), thereby regulating secondary signaling molecules within the cell. Examples of these molecules include cyclic adenosine monophosphate (cAMP), phosphatidylinositol diphosphate (IP3), and others.
- Downstream Signaling: The secondary signaling molecules activate a cascade of downstream signaling molecules, including protein kinases (such as protein kinase A, protein kinase C, mitogen-activated protein kinase, etc.) and signal transduction proteins (such as Ras, Rac, Cdc42, etc.). These molecules further regulate intracellular signal transmission.
- Cytoskeletal Rearrangement: Activation of the chemokine signaling pathway induces cytoskeletal rearrangement within cells. This includes the contraction and stretching of the cell membrane, remodeling of the cytoplasmic skeleton, and changes in cell shape.
Through these intricate signaling events, chemokines effectively regulate the directional movement and chemotactic responses of cells. These processes are critical for various physiological phenomena, including immune cell migration during inflammation, leukocyte chemotaxis, and tissue repair.
Clinical Significance of Chemokines: Implications in Immune Response and Disease
- Regulation of Immune Inflammation: Key Players in Inflammatory Processes
Chemokines play a pivotal role in the regulation of the inflammatory process. Their ability to attract immune cells, particularly white blood cells, to the site of inflammation is crucial for orchestrating and modulating inflammatory responses. By targeting the activity and signaling pathways of chemokines, it becomes possible to intervene in the development of immune-inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.
- Impact on Cancer Metastasis and Invasion: Implications for Disease Progression
Chemokines actively contribute to the metastasis and invasion of cancer cells into other tissues and organs, thereby playing a significant role in cancer progression. By interfering with the signaling and regulation of chemokines, it is possible to inhibit the metastasis and invasion of cancer cells, ultimately slowing down the development of cancer.
- Role in Wound Repair and Tissue Regeneration: Facilitating Healing Processes
Chemokines exert a profound impact on wound repair and tissue regeneration. They attract reparative cells and stem cells to migrate towards damaged tissues, thereby promoting the process of wound healing and tissue regeneration. By regulating the expression and activity of chemokines, it becomes possible to accelerate wound healing and tissue regeneration in various contexts, such as skin wound repair and nerve regeneration.
- Utilizing Chemokines in Immune Cell Therapy: Enhancing Treatment Strategies
Chemokines can serve as a valuable tool in immune cell therapy for the treatment of immune diseases and cancer. By utilizing chemokines to guide and enhance the migration and infiltration of immune cells, the therapeutic effect of these cells can be improved. For example, chemokines can be employed to direct the migration of tumor-infiltrating lymphocytes (TILs) and enhance the immune cells' ability to eliminate tumors, thus improving the efficacy of immune cell-based cancer therapies.
In general, chemokines are an important class of molecular signaling molecules that play an important role in immune response, inflammatory response and tissue repair. The study of chemokines and their receptors will help to understand the mechanism of inflammatory diseases and provide new targets and strategies for the treatment of related diseases.
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 Philip M. Murphy,10 - Chemokines and Chemokine Receptors,Clinical Immunology (Fifth Edition),Elsevier,2019,Pages 157-170.e1,ISBN 9780702068966