7.2 Chemokines and their receptors
3 min read•july 25, 2024
Chemokines are tiny proteins that play a big role in our immune system. They act like traffic cops, guiding immune cells to where they're needed most. From helping cells move during development to maintaining our body's defenses, chemokines are crucial for keeping us healthy.
There are different types of chemokines, each with its own job and receptor. CC chemokines attract certain immune cells, while CXC chemokines bring in others. These proteins create gradients that cells follow, like breadcrumbs leading them to the right spot. Understanding chemokines helps us fight diseases and develop new treatments.
Chemokine Fundamentals and Classification
Role of chemokines in immunity
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- Chemokines small secreted proteins 8-14 kDa direct cell movement function as chemoattractants (CCL2, )
- Guide leukocytes to specific tissues orchestrate immune responses (lymph nodes, infection sites)
- Direct cell migration during development shape lymphoid organ structure (thymus, bone marrow)
- Regulate homeostatic immune cell circulation maintain surveillance (blood, lymphatics)
- Bind to G protein-coupled receptors (GPCRs) trigger intracellular signaling cascades
- Induce cytoskeletal rearrangements promote cell polarization and directional movement
- Enhance integrin-mediated adhesion facilitate transendothelial migration
Chemokine subfamilies and receptors
- CC chemokines contain two adjacent cysteine residues attract monocytes, , (CCL2, , )
- - receptors mediate CC chemokine signaling regulate diverse immune functions
- CXC chemokines cysteine residues separated by one amino acid attract , lymphocytes (CXCL8, )
- - receptors mediate CXC chemokine signaling involved in inflammation, angiogenesis
- C chemokines single cysteine residue attract T cells and (XCL1, )
- receptor mediates C chemokine signaling expressed on dendritic cells
- CX3C chemokines three amino acids between cysteine residues unique membrane-bound form (CX3CL1)
- receptor mediates CX3C chemokine signaling expressed on monocytes, NK cells
Chemokine gradients for cell migration
- Concentration differences across tissues guide immune cells to specific locations
- Soluble chemokines diffuse through extracellular space create dynamic gradients
- Immobilized chemokines on extracellular matrix or cell surfaces form stable gradients
- Provide directional cues for cell movement enable precise navigation (inflammation sites)
- Facilitate positioning of immune cells within tissues organize lymphoid structures
- Cells sense gradients through differential receptor occupancy across cell surface
- Intracellular signaling cascades activated by receptor binding trigger directional responses
- Cytoskeletal reorganization in response to gradient leads to polarized cell movement
Chemokines in inflammation and disease
- Acute inflammation rapid recruitment of neutrophils and monocytes amplify immune response
- Induce adhesion molecule expression on endothelial cells facilitate leukocyte extravasation
- Chronic inflammation sustained recruitment of specific leukocyte subsets (T cells, )
- Contribute to tissue remodeling and fibrosis in prolonged inflammatory conditions
- Autoimmune diseases aberrant immune cell trafficking to target organs (joints, CNS)
- Cancer promote tumor cell migration and metastasis influence tumor microenvironment
- Recruit tumor-promoting immune cells (tumor-associated macrophages) suppress anti-tumor immunity
- Regulate angiogenesis influence tumor growth and spread
- Infectious diseases mediate host defense through leukocyte recruitment to infection sites
- Pathogens exploit chemokine receptors for entry and spread (HIV using CCR5)
- Chemokine receptor antagonists developed as anti-inflammatory drugs (CCR5 inhibitors for HIV)
- Modulation of chemokine signaling potential therapeutic strategy for various diseases
Key Terms to Review (28)
Autoimmunity: Autoimmunity is a condition where the immune system mistakenly targets and attacks the body's own healthy cells and tissues as if they were foreign invaders. This malfunction can lead to a variety of autoimmune diseases, where the immune response is directed against self-antigens, affecting overall health and well-being.
Ccl3: CCL3, also known as macrophage inflammatory protein-1 alpha (MIP-1α), is a type of chemokine that plays a vital role in immune responses by recruiting immune cells, particularly monocytes and T cells, to sites of inflammation. It is produced by various cell types, including activated macrophages and lymphocytes, and is crucial for orchestrating the immune response to infections and tissue injury.
CCL5: CCL5, also known as RANTES (Regulated upon Activation, Normal T Expressed and Secreted), is a chemokine involved in the recruitment and activation of immune cells, particularly T cells, eosinophils, and basophils. It plays a crucial role in immune responses by guiding these cells to sites of inflammation or infection, thereby influencing the overall adaptive immune response.
Ccr1: CCR1, or C-C Chemokine Receptor Type 1, is a receptor on the surface of immune cells that binds to specific chemokines, facilitating the migration of these cells to sites of inflammation or infection. This receptor plays a crucial role in regulating immune responses and mediating the movement of leukocytes, particularly monocytes and T cells, through the bloodstream to tissues where they are needed.
CCR10: CCR10, or C-C chemokine receptor type 10, is a specific receptor on the surface of immune cells that binds to chemokines, particularly CCL27. This interaction plays a crucial role in directing the migration of lymphocytes to sites of inflammation, especially in skin-associated tissues. The CCR10-CCL27 axis is important for immune responses, particularly in skin immunity and homeostasis.
Cell adhesion: Cell adhesion refers to the process by which cells interact and attach to neighboring cells or extracellular matrix components through specialized proteins. This interaction is essential for maintaining tissue structure, facilitating communication between cells, and regulating various biological processes such as immune response and inflammation.
Chemokine inhibitors: Chemokine inhibitors are substances that block the action of chemokines, which are signaling proteins crucial for immune cell migration and positioning within tissues. By preventing chemokines from binding to their receptors, these inhibitors can modulate immune responses, potentially benefiting conditions such as chronic inflammation and autoimmune diseases.
Chemotaxis: Chemotaxis is the movement of cells towards or away from a chemical stimulus, often used by immune cells to locate sites of infection or inflammation. This process is crucial for the functioning of the immune system, as it directs leukocytes to areas where they are needed most to fight off pathogens and initiate repair processes.
CX3CR1: CX3CR1 is a chemokine receptor that specifically binds to its ligand, fractalkine (CX3CL1), playing a vital role in the immune response by facilitating the movement of immune cells towards sites of inflammation. This receptor is predominantly expressed on monocytes, macrophages, and certain lymphocyte subsets, linking it closely to immune cell trafficking and interactions within tissues during both homeostasis and inflammatory conditions.
Cxcl12: CXCL12, also known as stromal-derived factor-1 (SDF-1), is a chemokine that plays a crucial role in the migration and homing of immune cells. It is produced by various cells in primary and secondary lymphoid organs and interacts with its receptor, CXCR4, to regulate the movement of lymphocytes and other immune cells during immune responses and development.
Cxcl8: CXCL8, also known as Interleukin-8 (IL-8), is a chemokine that primarily functions as a potent attractant for neutrophils and plays a key role in the immune response. It is produced by various cell types, including macrophages and endothelial cells, and its main function is to recruit immune cells to sites of inflammation, helping to facilitate the body's response to infection or injury.
Cxcr1: CXCR1 is a chemokine receptor that primarily binds to the chemokine interleukin-8 (IL-8), playing a crucial role in the recruitment and activation of neutrophils during inflammatory responses. This receptor is part of the G protein-coupled receptor family and facilitates important cellular processes such as chemotaxis, helping guide immune cells to sites of infection or injury.
Cxcr6: CXCR6 is a chemokine receptor that plays a crucial role in the immune response by guiding the migration of immune cells, particularly T cells and natural killer (NK) cells, to sites of inflammation and tissue damage. This receptor binds to its ligand, CXCL16, and is involved in various processes such as the regulation of immune surveillance and the inflammatory response.
Eosinophils: Eosinophils are a type of white blood cell that play a crucial role in the immune response, particularly in combating parasitic infections and participating in allergic reactions. These cells are characterized by their bilobed nucleus and distinctive granules that stain bright red with eosin dye, which is how they got their name. They contribute to innate immunity and can influence inflammation and tissue repair processes.
G-protein coupled receptor signaling: G-protein coupled receptor signaling is a crucial cellular communication mechanism that involves receptors that detect molecules outside the cell and activate internal signal transduction pathways. These receptors play a significant role in various physiological processes, including immune responses, by mediating the actions of chemokines through G-proteins, which are molecular switches that relay signals from activated receptors to various intracellular effectors.
Immune cell migration: Immune cell migration is the process by which immune cells move from one location to another in the body, often in response to infection or injury. This movement is crucial for mounting an effective immune response, as it allows immune cells to reach sites of inflammation, infection, or tissue damage, and carry out their functions. The regulation of this process involves various signaling molecules and receptors, particularly chemokines and their receptors, which guide immune cells to the correct locations.
Inflammatory response: The inflammatory response is a complex biological process initiated by the body in reaction to injury, infection, or harmful stimuli, characterized by redness, swelling, heat, and pain. This response serves to protect the body by eliminating the initial cause of cell injury, clearing out dead cells, and initiating tissue repair. It involves various immune cells and signaling molecules that help coordinate the body's defenses against pathogens and facilitate healing.
Ligand-receptor interaction: A ligand-receptor interaction is a biochemical event where a ligand, which can be a molecule like a hormone, neurotransmitter, or chemokine, binds to a specific receptor on a target cell, triggering a response in that cell. This process is crucial for cellular communication, enabling cells to respond to various signals and regulate immune responses, inflammation, and cellular migration.
Macrophages: Macrophages are large immune cells that play a crucial role in the body's defense mechanisms by engulfing and digesting cellular debris, pathogens, and foreign substances. They originate from monocytes in the blood and are pivotal in both the innate and adaptive immune responses, acting as key players in inflammation, antigen presentation, and tissue repair.
MAPK Pathway: The MAPK pathway, or Mitogen-Activated Protein Kinase pathway, is a signaling cascade that plays a crucial role in transmitting signals from cell surface receptors to the nucleus, leading to various cellular responses such as growth, differentiation, and apoptosis. This pathway is essential for T cell receptor signaling and chemokine receptor signaling, influencing T cell activation, proliferation, and migration.
Neutrophils: Neutrophils are a type of white blood cell that plays a vital role in the innate immune response, acting as the first line of defense against invading pathogens. They are essential for responding quickly to infections, especially bacterial and fungal, and are characterized by their ability to migrate to sites of inflammation and infection through the bloodstream and tissues.
Nk cells: Natural killer (NK) cells are a type of lymphocyte that plays a crucial role in the immune system by providing rapid responses to viral infections and controlling tumor formation. These cells are part of the innate immune response and can recognize and eliminate infected or cancerous cells without prior sensitization. Their activity is influenced by chemokines, which guide their movement to sites of infection or inflammation.
Phosphorylation: Phosphorylation is the process of adding a phosphate group (PO₄) to a molecule, typically a protein, which can alter its function and activity. This modification is crucial for many cellular processes, including signal transduction and the regulation of protein functions. By influencing the conformation and activity of proteins, phosphorylation plays a significant role in cellular communication, particularly in response to chemokines and their receptors.
Pi3k pathway: The PI3K pathway, or Phosphoinositide 3-kinase pathway, is a critical signaling cascade that regulates various cellular functions, including growth, proliferation, and survival. It is activated by various receptors, including those on T cells and B cells, and plays a significant role in immune responses and cell signaling through the generation of lipid second messengers.
T cells: T cells, or T lymphocytes, are a type of white blood cell that plays a central role in the adaptive immune response. They originate from hematopoietic stem cells in the bone marrow but mature in the thymus, where they develop the ability to recognize specific antigens presented by other cells. T cells are crucial for cell-mediated immunity, helping to eliminate infected or cancerous cells and orchestrating the immune response.
Targeted immunotherapy: Targeted immunotherapy is a form of cancer treatment that uses the body's immune system to specifically target and attack cancer cells while minimizing damage to normal cells. This approach focuses on identifying specific molecules or markers on cancer cells, such as antigens, and utilizing therapies that enhance the immune response against those targets. By honing in on particular pathways and interactions, targeted immunotherapy aims to improve treatment efficacy and reduce side effects compared to traditional therapies.
XCL2: XCL2, also known as lymphotactin, is a chemokine that primarily attracts lymphocytes and is crucial in immune responses. It interacts specifically with its receptor XCR1, facilitating the movement of T cells and other immune cells to sites of inflammation or infection, thus playing an essential role in the body’s defense mechanism.
Xcr1: xcr1 is a chemokine receptor that is primarily expressed on the surface of specific immune cells, particularly plasmacytoid dendritic cells (pDCs). This receptor plays a vital role in mediating the migration of these cells to sites of infection or inflammation, as it responds to its ligand, XCL1, which is produced by activated T cells and other immune cells. By facilitating this migration, xcr1 contributes to the coordination of the immune response, enhancing the body's ability to combat pathogens.