Innate immune system

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https://en.wikipedia.org/wiki/Innate_immune_system 

 

Innate immune system

The innate immune system is one of the two main immunity strategies found in vertebrates (the other being the adaptive immune system). The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

The major functions of the vertebrate innate immune system include:

• Recruiting immune cells to sites of infection through the production of chemical factors, including specialized chemical mediators called cytokines
• Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells
• Identification and removal of foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells
• Activation of the adaptive immune system through a process known as antigen presentation
• Acting as a physical and chemical barrier to infectious agents; via physical measures like skin or tree bark and chemical measures like clotting factors in blood or sap from a tree, which are released following a contusion or other injury that breaks through the first-line physical barrier (not to be confused with a second-line physical or chemical barrier, such as the blood-brain barrier, which protects the extremely vital and highly sensitive nervous system from pathogens that have already gained access to the host's body).

Anatomical barriers

Anatomical barrier	Additional defense mechanisms
Skin	Sweat, desquamation, flushing, organic acids
Gastrointestinal tract	Peristalsis, gastric acid, bile acids, digestive enzyme, flushing, thiocyanate, defensins, gut flora
Respiratory airways and lungs	Mucociliary escalator, surfactant, defensins
Nasopharynx	Mucus, saliva, lysozyme
Eyes	Tears
Blood-brain barrier	endothelial cells (via passive diffusion / osmosis & active selection). P-glycoprotein (mechanism by which active transportation is mediated)

Anatomical barriers include physical, chemical and biological barriers. The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line of defense against invading organisms. Desquamation (shedding) of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. Lack of blood vessels, the inability of the epidermis to retain moisture, and the presence of sebaceous glands in the dermis, produces an environment unsuitable for the survival of microbes. In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious agents. Also, mucus traps infectious agents. The gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces. The flushing action of tears and saliva helps prevent infection of the eyes and mouth.

Inflammation

Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, and mast cells. These cells present receptors contained on the surface or within the cell, named pattern recognition receptors (PRRs), which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRRs recognizes a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation.

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes, and prostaglandins) sensitize pain receptors, cause local vasodilation of the blood vessels, and attract phagocytes, especially neutrophils. Neutrophils then trigger other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes. Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response. These cytokines include TNF, HMGB1, and IL-1.

The inflammatory response is characterized by the following symptoms:

• redness of the skin, due to locally increased blood circulation;
• heat, either increased local temperature, such as a warm feeling around a localized infection, or a systemic fever;
• swelling of affected tissues, such as the upper throat during the common cold or joints affected by rheumatoid arthritis;
• increased production of mucus, which can cause symptoms like a runny nose or a productive cough;
• pain, either local pain, such as painful joints or a sore throat, or affecting the whole body, such as body aches; and
• possible dysfunction of the organs or tissues involved.

Complement system

The complement system is a biochemical cascade of the immune system that helps, or “complements”, the ability of antibodies to clear pathogens or mark them for destruction by other cells. The cascade is composed of many plasma proteins, synthesized in the liver, primarily by hepatocytes. The proteins work together to:

• trigger the recruitment of inflammatory cells
• "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen
• form holes in the plasma membrane of the pathogen, resulting in cytolysis of the pathogen cell, causing the death of the pathogen
• rid the body of neutralised antigen-antibody complexes.

There are three different complement systems: Classical, alternative, Lectin

• Classical: starts when antibody bind to bacteria
• Alternative: starts "spontaneously"
• Lectin: starts when lectins bind to mannose on bacteria

Elements of the complement cascade can be found in many non-mammalian species including plants, birds, fish, and some species of invertebrates.

White blood cells

A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shape platelets.

 

All white blood cells (WBCs) are known as leukocytes. Most leukocytes differ from other cells of the body in that they are not tightly associated with a particular organ or tissue; thus, their function is similar to that of independent, single-cell organisms. Most leukocytes are able to move freely and interact with and capture cellular debris, foreign particles, and invading microorganisms (although macrophages, mast cells, and dendritic cells are less mobile). Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of multipotent hematopoietic stem cells present in the bone marrow.

The innate leukocytes include: natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells include macrophages, neutrophils, and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.

Mast cells

Mast cells are a type of innate immune cell that reside in connective tissue and in the mucous membranes. They are intimately associated with wound healing and defense against pathogens, but are also often associated with allergy and anaphylaxis (serious allergic reactions that can cause death). When activated, mast cells rapidly release characteristic granules, rich in histamine and heparin, along with various hormonal mediators and chemokines, or chemotactic cytokines into the environment. Histamine dilates blood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.

Phagocytes

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or 'phagocytose', pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its plasma membrane, wrapping the membrane around the particle until it is enveloped (i.e., the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside a phagosome, which merges with a lysosome. The lysosome contains enzymes and acids that kill and digest the particle or organism. In general, phagocytes patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. The phagocytic cells of the immune system include macrophages, neutrophils, and dendritic cells. 

Phagocytosis of the hosts’ own cells is common as part of regular tissue development and maintenance. When host cells die, either by programmed cell death (also called apoptosis) or by cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal from the affected site. By helping to remove dead cells preceding growth and development of new healthy cells, phagocytosis is an important part of the healing process following tissue injury.

A macrophage

Macrophages

Macrophages, from the Greek, meaning "large eaters," are large phagocytic leukocytes, which are able to move outside of the vascular system by migrating through the walls of capillary vessels and entering the areas between cells in pursuit of invading pathogens. In tissues, organ-specific macrophages are differentiated from phagocytic cells present in the blood called monocytes. Macrophages are the most efficient phagocytes and can phagocytose substantial numbers of bacteria or other cells or microbes. The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a “respiratory burst”, causing the release of reactive oxygen species. Pathogens also stimulate the macrophage to produce chemokines, which summon other cells to the site of infection.

Neutrophils

A neutrophil

Neutrophils, along with two other cell types (eosinophils and basophils; see below), are known as granulocytes due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobed nuclei. Neutrophil granules contain a variety of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to macrophages, neutrophils attack pathogens by activating a respiratory burst. The main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50-60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection. The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day during acute inflammation.

Dendritic cells

Dendritic cells (DCs) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), and the inner mucosal lining of the nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, but dendritic cells are not connected to the nervous system. Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive immune systems.

An eosinophil

Basophils and eosinophils

Basophils and eosinophils are cells related to the neutrophil (see above). When activated by a pathogen encounter, histamine-releasing basophils are important in the defense against parasites and play a role in allergic reactions, such as asthma. Upon activation, eosinophils secrete a range of highly toxic proteins and free radicals that are highly effective in killing parasites, but may also damage tissue during an allergic reaction. Activation and release of toxins by eosinophils are, therefore, tightly regulated to prevent any inappropriate tissue destruction.

Natural killer cells

Natural killer cells (NK cells) are a component of the innate immune system that does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with abnormally low levels of a cell-surface marker called MHC I (major histocompatibility complex) - a situation that can arise in viral infections of host cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years, it was unclear how NK cell recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) that, in essence, put the brakes on NK cells. The NK-92 cell line does not express KIR and is developed for tumor therapy.^[11][12]

γδ T cells

Like other 'unconventional' T cell subsets bearing invariant T cell receptors (TCRs), such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells.

Other vertebrate mechanisms

The coagulation system overlaps with the immune system. Some products of the coagulation system can contribute to the non-specific defenses by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, a protein produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent. Many acute-phase proteins of inflammation are involved in the coagulation system.

Also increased levels of lactoferrin and transferrin inhibit bacterial growth by binding iron, an essential nutrient for bacteria.

Neural regulation

The innate immune response to infectious and sterile injury is modulated by neural circuits that control cytokine production period. The inflammatory reflex is a prototypical neural circuit that controls cytokine production in the spleen. Action potentials transmitted via the vagus nerve to spleen mediate the release of acetylcholine, the neurotransmitter that inhibits cytokine release by interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokine-producing cells. The motor arc of the inflammatory reflex is termed the cholinergic anti-inflammatory pathway.

Pathogen-specificity

The parts of the innate immune system have different specificity for different pathogens. 

Pathogen	Main examples	Phagocytosis	complement	NK cells
Intracellular and cytoplasmic virus	influenza mumps measles rhinovirus	yes	no	yes
Intracellular bacteria	Listeria monocytogenes Legionella Mycobacterium Rickettsia	yes (specifically neutrophils, no for rickettsia)	no	yes (no for rickettsia)
Extracellular bacteria	Staphylococcus Streptococcus Neisseria Salmonella typhi	yes	yes	no
Intracellular protozoa	Plasmodium malariae Leishmania donovani	no	no	no
Extracellular protozoa	Entamoeba histolytica Giardia lamblia	yes	yes	no
Extracellular fungi	Candida Histoplasma Cryptococcus	no	yes	yes

Immune evasion

Cells of the innate immune system prevent free growth of microorganisms within the body, but many pathogens have evolved mechanisms to evade it.

One strategy is intracellular replication, as practised by Mycobacterium tuberculosis, or wearing a protective capsule, which prevents lysis by complement and by phagocytes, as in Salmonella. Bacteroides species are normally mutualistic bacteria, making up a substantial portion of the mammalian gastrointestinal flora. Some species like B. fragilis for example are opportunistic pathogens, causing infections of the peritoneal cavity inhibit phagocytosis by affecting the phagocytes receptors used to engulf bacteria. They may also mimick host cells so the immune system does not recognize them as foreign. Staphylococcus aureus inhibits the ability of the phagocyte to respond to chemokine signals. M. tuberculosis, Streptococcus pyogenes, and Bacillus anthracis utilize mechanisms that directly kill the phagocyte.

Bacteria and fungi may form complex biofilms, protecting from immune cells and proteins; biofilms are present in the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.

Viruses

Type I interferons (IFN), secreted mainly by dendritic cells, play a central role in antiviral host defense and a cell's antiviral state. Viral components are recognized by different receptors: Toll-like receptors are located in the endosomal membrane and recognize double-stranded RNA (dsRNA), MDA5 and RIG-I receptors are located in the cytoplasm and recognize long dsRNA and phosphate-containing dsRNA respectively. When the cytoplasmic receptors MDA5 and RIG-I recognize a virus the conformation between the caspase-recruitment domain (CARD) and the CARD-containing adaptor MAVS changes. In parallel, when toll-like receptors in the endocytic compartments recognize a virus the activation of the adaptor protein TRIF is induced. Both pathways converge in the recruitment and activation of the IKKε/TBK-1 complex, inducing dimerization of transcription factors IRF3 and IRF7, which are translocated in the nucleus, where they induce IFN production with the presence of a particular transcription factor and activate transcription factor 2. IFN is secreted through secretory vesicles, where it can activate receptors on both the same cell it was released from (autocrine) or nearby cells (paracrine). This induces hundreds of interferon-stimulated genes to be expressed. This leads to antiviral protein production, such as protein kinase R, which inhibits viral protein synthesis, or the 2′,5′-oligoadenylate synthetase family, which degrades viral RNA.

Some viruses evade this by producing molecules which interfere with IFN production. For example, the Influenza A virus produces NS1 protein, which can bind to host and viral RNA, interact with immune signaling proteins or block their activation by ubiquitination, thus inhibiting type I IFN production. Influenza A also blocks protein kinase R activation and establishment of the antiviral state. The dengue virus also inhibits type I IFN production by blocking IRF-3 phosophorylation using NS2B3 protease complex.

In other species

Prokaryotes

Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism, called the restriction modification system to protect themselves from pathogens, such as bacteriophages. In this system, bacteria produce enzymes, called restriction endonucleases, that attack and destroy specific regions of the viral DNA of invading bacteriophages. Methylation of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases. Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes.

Invertebrates

Invertebrates do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates. Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists in all coelomates (animals with a body-cavity), including humans. The complement system, as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, crabs, and worms utilize a modified form of the complement response known as the prophenoloxidase (proPO) system.

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic immunity. Several species of insect produce antimicrobial peptides known as defensins and cecropins.

Proteolytic cascades

In invertebrates, pattern recognition proteins (PRPs) trigger proteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—including hemolymph coagulation and melanization. Proteolytic cascades are important components of the invertebrate immune system because they are turned on more rapidly than other innate immune reactions because they do not rely on gene changes. Proteolytic cascades have been found to function the same in both vertebrate and invertebrates, even though different proteins are used throughout the cascades.

Clotting mechanisms

In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are various different proteins and mechanisms that are involved in invertebrate clotting. In crustaceans, transglutaminase from blood cells and mobile plasma proteins make up the clotting system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein. On the other hand, in the horseshoe crab species clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, like lipopolysaccharides enter.

Plants

Members of every class of pathogen that infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes, and insects can all cause plant disease. As with animals, plants attacked by insects or other pathogens use a set of complex metabolic responses which lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other herbivores.

Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection.

Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to recognize conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved microbial signatures were identified in rice (XA21, 1995) and in Arabidopsis (FLS2, 2000). Plants also carry immune receptors that recognize highly variable pathogen effectors. These include the NBS-LRR class of proteins. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specific elicitors, the plant produces a localized hypersensitive response (HR), in which cells at the site of infection undergo rapid programmed cell death to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic activity of VPEγ, a cysteine protease that regulates cell disassembly during cell death.

"Resistance" (R) proteins, encoded by R genes, are widely present in plants and detect pathogens. These proteins contain domains similar to the NOD Like Receptors and Toll-like receptors utilized in animal innate immunity. Systemic acquired resistance (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents. SAR involves the production of chemical messengers, such as salicylic acid or jasmonic acid. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves. Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role for jasmonates in transmission of the signal to distal portions of the plant. RNA silencing mechanisms are also important in the plant systemic response, as they can block virus replication. The jasmonic acid response, is stimulated in leaves damaged by insects, and involves the production of methyl jasmonate.

Chemokine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Chemokine

 

Small cytokines (intecrine/chemokine), interleukin-8 like
Solution structure of interleukin-8, a chemokine of the CXC subfamily
Identifiers
Symbol	IL8
Pfam	PF00048
InterPro	IPR001811
PROSITE	PDOC00434
SCOPe	3il8 / SUPFAM

Chemokines (Greek -kinos, movement) are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

Cytokine proteins are classified as chemokines according to behavior and structural characteristics. In addition to being known for mediating chemotaxis, chemokines are all approximately 8-10 kilodaltons in mass and have four cysteine residues in conserved locations that are key to forming their 3-dimensional shape.

These proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been found in other invertebrates.

Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and XC. All of these proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.

Function

Chemokines released by infected or damaged cells form a concentration gradient. Attracted cells move through the gradient towards the higher concentration of chemokine.

The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the immune system during processes of immune surveillance, such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. These are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cell(s). Some chemokines have roles in development; they promote angiogenesis (the growth of new blood vessels), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout. Their release is often stimulated by pro-inflammatory cytokines such as interleukin 1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system.

Types by function

Chemokines are functionally divided into two groups:

• Homeostatic: are constitutively produced in certain tissues and are responsible for basal leukocyte migration. These include: CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13. This classification is not strict; for example, CCL20 can act also as pro-inflammatory chemokine.
• Inflammatory: these are formed under pathological conditions (on pro-inflammatory stimuli, such as IL-1, TNF-alpha, LPS, or viruses) and actively participate in the inflammatory response attracting immune cells to the site of inflammation. Examples are: CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10.

Homing

The main function of chemokines is to manage the migration of leukocytes (homing) in the respective anatomical locations in inflammatory and homeostatic processes. 

Basal: homeostatic chemokines are basal produced in the thymus and lymphoid tissues. Their homeostatic function in homing is best exemplified by the chemokines CCL19 and CCL21 (expressed within lymph nodes and on lymphatic endothelial cells) and their receptor CCR7 (expressed on cells destined for homing in cells to these organs). Using these ligands is possible routing antigen-presenting cells (APC) to lymph nodes during the adaptive immune response. Among other homeostatic chemokine receptors include: CCR9, CCR10, and CXCR5, which are important as part of the cell addresses for tissue-specific homing of leukocytes. CCR9 supports the migration of leukocytes into the intestine, CCR10 to the skin and CXCR5 supports the migration of B-cell to follicles of lymph nodes. As well CXCL12 (SDF-1) constitutively produced in the bone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment.

Inflammatory: inflammatory chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes into the damaged area. Typical inflammatory chemokines include: CCL2, CCL3 and CCL5, CXCL1, CXCL2 and CXCL8. A typical example is CXCL-8, which acts as a chemoattractant for neutrophils. In contrast to the homeostatic chemokine receptors, there is significant promiscuity (redundancy) associated with binding receptor and inflammatory chemokines. This often complicates research on receptor-specific therapeutics in this area.

Types by cell attracted

• Monocytes / macrophages: the key chemokines that attract these cells to the site of inflammation include: CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17 and CCL22.
• T-lymphocytes: the four key chemokines that are involved in the recruitment of T lymphocytes to the site of inflammation are: CCL2, CCL1, CCL22 and CCL17. Furthermore, CXCR3 expression by T-cells is induced following T-cell activation and activated T-cells are attracted to sites of inflammation where the IFN-y inducible chemokines CXCL9, CXCL10 and CXCL11 are secreted.
• Mast cells: on their surface express several receptors for chemokines: CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Ligands of these receptors CCL2 and CCL5 play an important role in mast cell recruitment and activation in the lung.There is also evidence that CXCL8 might be inhibitory of mast cells.
• Eosinophils: the migration of eosinophils into various tissues involved several chemokines of CC family: CCL11, CCL24, CCL26, CCL5, CCL7, CCL13, and CCL3. Chemokines CCL11 (eotaxin) and CCL5 (RANTES) acts through a specific receptor CCR3 on the surface of eosinophils, and eotaxin plays an essential role in the initial recruitment of eosinophils into the lesion.
• Neutrophils: are regulated primarily by CXC chemokines. An example CXCL8 (IL-8) is chemoattractant for neutrophils and also activating their metabolic and degranulation.

Structural characteristics

All chemokines share a typical Greek key structure that is stabilised by disulfide bonds between conserved cysteine residues.

 

Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with a molecular mass of between 8 and 10 kDa. They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that is a characteristic of chemokines. Intramolecular disulfide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine. Typical chemokine proteins are produced as pro-peptides, beginning with a signal peptide of approximately 20 amino acids that gets cleaved from the active (mature) portion of the molecule during the process of its secretion from the cell. The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end. A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop. This is followed by a single-turn helix, called a 3₁₀-helix, three β-strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops.

Types by structure

CC chemokines
Name	Gene	Other name(s)	Receptor	Uniprot
CCL1	Scya1	I-309, TCA-3	CCR8
CCL2	Scya2	MCP-1	CCR2	P13500
CCL3	Scya3	MIP-1a	CCR1	P10147
CCL4	Scya4	MIP-1β	CCR1, CCR5	P13236
CCL5	Scya5	RANTES	CCR5	P13501
CCL6	Scya6	C10, MRP-2	CCR1	P27784
CCL7	Scya7	MARC, MCP-3	CCR2	P80098
CCL8	Scya8	MCP-2	CCR1, CCR2, CCR5	P80075
CCL9/CCL10	Scya9	MRP-2, CCF18, MIP-1?	CCR1	P51670
CCL11	Scya11	Eotaxin	CCR2, CCR3, CCR5	P51671
CCL12	Scya12	MCP-5		Q62401
CCL13	Scya13	MCP-4, NCC-1, Ckβ10	CCR2, CCR3, CCR5	Q99616
CCL14	Scya14	HCC-1, MCIF, Ckβ1, NCC-2, CCL	CCR1	Q16627
CCL15	Scya15	Leukotactin-1, MIP-5, HCC-2, NCC-3	CCR1, CCR3	Q16663
CCL16	Scya16	LEC, NCC-4, LMC, Ckβ12	CCR1, CCR2, CCR5, CCR8	O15467
CCL17	Scya17	TARC, dendrokine, ABCD-2	CCR4	Q92583
CCL18	Scya18	PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4		P55774
CCL19	Scya19	ELC, Exodus-3, Ckβ11	CCR7	Q99731
CCL20	Scya20	LARC, Exodus-1, Ckβ4	CCR6	P78556
CCL21	Scya21	SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4	CCR7	O00585
CCL22	Scya22	MDC, DC/β-CK	CCR4	O00626
CCL23	Scya23	MPIF-1, Ckβ8, MIP-3, MPIF-1	CCR1	P55773
CCL24	Scya24	Eotaxin-2, MPIF-2, Ckβ6	CCR3	O00175
CCL25	Scya25	TECK, Ckβ15	CCR9	O15444
CCL26	Scya26	Eotaxin-3, MIP-4a, IMAC, TSC-1	CCR3	Q9Y258
CCL27	Scya27	CTACK, ILC, Eskine, PESKY, skinkine	CCR10	Q9Y4X3
CCL28	Scya28	MEC	CCR3, CCR10	Q9NRJ3
CXC chemokines
Name	Gene	Other name(s)	Receptor	Uniprot
CXCL1	Scyb1	Gro-a, GRO1, NAP-3, KC	CXCR2	P09341
CXCL2	Scyb2	Gro-β, GRO2, MIP-2a	CXCR2	P19875
CXCL3	Scyb3	Gro-?, GRO3, MIP-2β	CXCR2	P19876
CXCL4	Scyb4	PF-4	CXCR3B	P02776
CXCL5	Scyb5	ENA-78	CXCR2	P42830
CXCL6	Scyb6	GCP-2	CXCR1, CXCR2	P80162
CXCL7	Scyb7	NAP-2, CTAPIII, β-Ta, PEP		P02775
CXCL8	Scyb8	IL-8, NAP-1, MDNCF, GCP-1	CXCR1, CXCR2	P10145
CXCL9	Scyb9	MIG, CRG-10	CXCR3	Q07325
CXCL10	Scyb10	IP-10, CRG-2	CXCR3	P02778
CXCL11	Scyb11	I-TAC, β-R1, IP-9	CXCR3, CXCR7	O14625
CXCL12	Scyb12	SDF-1, PBSF	CXCR4, CXCR7	P48061
CXCL13	Scyb13	BCA-1, BLC	CXCR5	O43927
CXCL14	Scyb14	BRAK, bolekine		O95715
CXCL15	Scyb15	Lungkine, WECHE		Q9WVL7
CXCL16	Scyb16	SRPSOX	CXCR6	Q9H2A7
CXCL17	VCC-1	DMC, VCC-1		Q6UXB2
C chemokines
Name	Gene	Other name(s)	Receptor	Uniprot
XCL1	Scyc1	Lymphotactin a, SCM-1a, ATAC	XCR1	P47992
XCL2	Scyc2	Lymphotactin β, SCM-1β	XCR1	Q9UBD3
CX3C chemokines
Name	Gene	Other name(s)	Receptor	Uniprot
CX3CL1	Scyd1	Fractalkine, Neurotactin, ABCD-3	CX3CR1	P78423

Members of the chemokine family are divided into four groups depending on the spacing of their first two cysteine residues. Thus the nomenclature for chemokines is, e.g.: CCL1 for the ligand 1 of the CC-family of chemokines, and CCR1 for its respective receptor.

CC chemokines

The CC chemokine (or β-chemokine) proteins have two adjacent cysteines (amino acids), near their amino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28; CCL10 is the same as CCL9. Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28. CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells.

Examples of CC chemokine include monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages.

CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5.

Increased CCL11 levels in blood plasma are associated with aging (and reduced neurogenesis) in mice and humans.

CXC chemokines

The two N-terminal cysteines of CXC chemokines (or α-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of glutamic acid-leucine-arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7.

C chemokines

The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 (lymphotactin-α) and XCL2 (lymphotactin-β).

CX₃C chemokines

A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX₃C chemokine (or d-chemokines). The only CX₃C chemokine discovered to date is called fractalkine (or CX₃CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an adhesion molecule.

Receptors

Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.

Signal transduction

Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor.

Infection control

The discovery that the β chemokines RANTES, MIP (macrophage inflammatory proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo, and that sustained delivery of such inhibitors have the capacity of long-term infection control. The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.