Leukocyte extravasation is the movement of leukocytes out of the circulatory system

Circulatory system

The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

, towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

Overview

Leukocyte extravasation occurs mainly in post-capillary venules, where haemodynamic shear forces

Shear stress

A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...

 are minimised. This process can be understood in several steps, outlined below as "chemoattraction", "rolling adhesion", "tight adhesion" and "(endothelial) transmigration". It has been demonstrated that leukocyte recruitment is halted whenever any of these steps is suppressed.

Chemoattraction

Upon recognition of and activation by pathogens, resident macrophages in the affected tissue release cytokines such as IL-1

IL-1

IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....

, TNFα and chemokines. IL-1 and TNFα cause the endothelial cells of blood vessels near the site of infection to express cellular adhesion molecules, including selectins. Circulating leukocytes are localised towards the site of injury or infection due to the presence of chemokines.

Rolling adhesion

Like velcro, carbohydrate ligands on the circulating leukocytes bind to selectin molecules on the inner wall of the vessel, with marginal affinity. This causes the leukocytes to slow down and begin rolling along the inner surface of the vessel wall. During this rolling motion, transitory bonds are formed and broken between selectins and their ligands.

Tight adhesion

At the same time, chemokines released by macrophages activate the rolling leukocytes and cause surface integrin

Integrin

Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....

 molecules to switch from the default low-affinity state to a high-affinity state. This is assisted through juxtacrine activation of integrins by chemokines and soluble factors released by endothelial cells. In the activated state, integrins bind tightly to complementary receptors expressed on endothelial cells, with high affinity. This causes the immobilisation of the leukocytes, despite the shear forces of the ongoing blood flow.

Transmigration

The cytoskeleton

Cytoskeleton

The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

s of the leukocytes are reorganised in such a way that the leukocytes are spread out over the endothelial cells. In this form, leukocytes extend pseudopodia and pass through gaps between endothelial cells. Transmigration of the leukocyte occurs as PECAM proteins, found on the leukocyte and endothelial cell surfaces, interact and effectively pull the cell through the endothelium. Once through the endothelium, the leukocyte must penetrate the basement membrane

Basement membrane

The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...

. The mechanism for penetration is disputed, but may involve proteolytic digestion of the membrane, mechanical force, or both. The entire process of blood vessel escape is known as diapedesis. Once in the interstitial fluid

Interstitial fluid

Interstitial fluid is a solution that bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular fluid...

, leukocytes migrate along a chemotactic

Chemotaxis

Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

 gradient towards the site of injury or infection.

Selectins

Selectins are expressed shortly after cytokine activation of endothelial cells by tissue macrophages. Activated endothelial cells initially express P-selectin molecules, but within two hours after activation E-selectin expression is favoured. Endothelial selectins bind carbohydrates on leukocyte transmembrane glycoproteins, including sialyl-Lewis^X

Sialyl lewis x

Sialyl LewisX, also known as sialyl LeX and SLeX, is a tetrasaccharide carbohydrate that is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means in which an egg attracts sperm - first to stick to it,...

.

• P-selectin
  P-selectin
  P-selectin is a cell adhesion molecule on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets...
  
  s: P-selectin is expressed on activated endothelial cells and platelets. Synthesis of P-selectin can be induced by thrombin
  Thrombin
  Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
  
  , leukotriene
  Leukotriene
  Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
  
   B4, complement
  Complement system
  The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
  
   fragment C5a
  C5a
  C5a is a protein fragment released from complement component C5. In humans, the polypeptide contains 74 amino acids. NMR spectroscopy proved that the molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present. The longest helix...
  
  , histamine
  Histamine
  Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
  
  , TNFα or LPS
  Lipopolysaccharide
  Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
  
  . These cytokines induce the externalisation of Weibel-Palade bodies in endothelial cells, presenting pre-formed P-selectins on the endothelial cell surface. P-selectins bind PSGL-1 as a ligand.
• E-selectin
  E-selectin
  E-selectin, also known as CD62 antigen-like family member E , endothelial-leukocyte adhesion molecule 1 , or leukocyte-endothelial cell adhesion molecule 2 , is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in...
  
  s: E-selectin is expressed on activated endothelial cells. Synthesis of E-selectin follows shortly after P-selectin synthesis, induced by cytokines such as IL-1 and TNFα. E-selectins bind PSGL-1 and ESL-1.
• L-selectin
  L-selectin
  L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups...
  
  s: L-selectins are constitutively expressed on some leukocytes, and are known to bind GlyCAM-1, MadCAM-1 and CD34
  CD34
  CD34 molecule is a cluster of differentiation molecule present on certain cells within the human body. It is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells...
  
   as ligands.

Suppressed expression of some selectins results in a slower immune response. If L-selectin is not produced, the immune response may be ten times slower, as P-selectins (which can also be produced by leukocytes) bind to each other. P-selectins can bind each other with high affinity, but occur less frequently because the receptor-site density is lower than with the smaller E-selectin molecules. This increases the initial leukocyte rolling speed, prolonging the slow rolling phase.

Integrins

Integrins involved in cellular adhesion are primarily expressed on leukocytes. β2 integrins on rolling leukocytes bind endothelial cellular adhesion molecules, arresting cell movement.

• LFA-1
  LFA-1
  Lymphocyte function-associated antigen 1, also known as LFA-1 is found on all T-cells and also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule. LFA-1 is the first...
  
  is found on circulating leukocytes, and binds ICAM-1
  ICAM-1
  ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system...
  
   and ICAM-2 on endothelial cells
• Mac-1
  Mac-1
  MAC-1 may refer to:* Macrophage-1 antigen* Integrin alpha M...
  
  is found on circulating leukocytes, and binds ICAM-1 on endothelial cells
• VLA-4 is found on leukocytes and endothelial cells, and facilitates chemotaxis; it also binds VCAM-1
  VCAM-1
  Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 or cluster of differentiation 106 is a protein that in humans is encoded by the VCAM1 gene...
  
  

Cellular activation via extracellular chemokines causes pre-formed β2 integrins to be released from cellular stores. Integrin molecules migrate to the cell surface and congregate in high-avidity

Avidity

In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...

 patches. Intracellular integrin domains associate with the leukocyte cytoskeleton, via mediation with cytosolic factors such as talin, α-actinin and vinculin

Vinculin

In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton...

. This association causes a conformational shift in the integrin's tertiary structure

Tertiary structure

In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...

, allowing ligand access to the binding site. Divalent cations

Divalent

In chemistry, a divalent ion or molecule has a valence of two and thus can form two bonds with other ions or molecules. An older term for divalent is bivalent....

 (e.g. Mg²⁺

Magnesium

Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...

) are also required for integrin-ligand binding.

Integrin ligands ICAM-1 and VCAM-1 are activated by inflammatory cytokines, while ICAM-2 is constitutively expressed by some endothelial cells but downregulated by inflammatory cytokines. ICAM-1 and ICAM-2 share two homologous N-terminal

N-terminal end

The N-terminus refers to the start of a protein or polypeptide terminated by an amino acid with a free amine group . The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus...

 domains; both can bind LFA-1.

During chemotaxis, cell movement is facilitated by the binding of β1 integrins to components of the extracellular matrix

Extracellular matrix

In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

: VLA-3, VLA-4 and VLA-5 to fibronectin

Fibronectin

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

 and VLA-2 and VLA-3 to collagen

Collagen

Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 and other extracellular matrix components.

Cytokines

Extravasation is regulated by the background cytokine environment produced by the inflammatory response, and is independent of specific cellular antigens. Cytokines released in the initial immune response induce vasodilation

Vasodilation

Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

 and lower the electrical charge along the vessel's surface. Blood flow is slowed, facilitating intermolecular binding.

• IL-1
  IL-1
  IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
  
  activates resident lymphocytes and vascular endothelia
• TNFα increases vascular permeability and activates vascular endothelia
• CXCL8 (IL-8) forms a chemotactic gradient that directs leukocytes towards site of tissue injury/infection (CCL2
  CCL2
  For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...
  
   has a similar function to CXCL8, inducing monocyte extravasation and development into macrophages); also activates leukocyte integrins

Leukocyte adhesion deficiency

Leukocyte adhesion deficiency (LAD) is a genetic disease associated with a defect in the leukocyte extravasation process, caused by a defective integrin β2 chain (found in LFA-1 and Mac-1). This impairs the ability of the leukocytes to stop and undergo diapedesis. People with LAD suffer from recurrent bacterial infections and impaired wound healing. Neutrophilia

Neutrophilia

Neutrophilia is a condition where a person has a high number of neutrophil granulocytes in their blood.-Causes:...

is a hallmark of LAD.

External links

• Animation of the adhesion process