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Created page with "Neutrophils are normally confined to the bloodstream and circulate with the other blood cells. If they are to defend tissues against a microbial invasion, they must leave the..."
Neutrophils are normally confined to the bloodstream and circulate with the other blood cells. If they are to defend tissues against a microbial invasion, they must leave the bloodstream. in normal tissues, neutrophils are carried along by the flow, like other blood cells. In inflamed tissues these fast-moving cells must slow down, stop, bind to blood vessel walls, and then must leave blood vessels by emigration through the vessel walls. This emigration is triggered by changes both in the endothelial cells that line blood vessel walls and in the neutrophils themselves.
== Changes in Endothelial Cells==
Bacterial products such as LPS, or alarmins from damaged tissues such as thrombin or histamine, cause capillary endothelial cells to express a glycoprotein called P-selectin (CD62P). P-selectin is normally stored in granules, but it moves to the endothelial cell surface within minutes after cell stimulation. Once expressed on the endothelial cell surface, the P-selectin binds to a protein called L-selectin (CD62L) on the surface of passing neutrophils. This binding is transient because the neutrophils readily shed their L-selectin. Nevertheless, the neutrophils gradually slow down and roll along the endothelial cell surface as they lose speed and eventually come to a complete stop.
== Changes in Neutrophils ==
As the neutrophils roll along the endothelial surface, the second stage of adhesion occurs. Platelet-activating factor secreted by the endothelial cells activates the rolling neutrophils so that they express a protein called CD11a/CD18 or LFA-1 (leukocyte function-associated antigen-1). LFA-1 is an adhesive protein or integrin, and it binds strongly to a glycoprotein called intracellular adhesion molecule-1 (ICAM-1 or CD54) expressed on the endothelial cells. This strong binding makes the neutrophil come to a complete stop and attaches it firmly to the vessel wall despite the shearing force of the blood flow. Adherent neutrophils also secrete small amounts of elastase. The elastase removes CD43 (leukosialin), an anti-adhesive protein, from the neutrophil surface, which allows the neutrophils to bind to the endothelial cells even more strongly. A third stage of increased leukocyte-endothelial cell adhesion takes several hours to develop and is mediated by cytokines and chemokines. Thus endothelial cells activated by interleukin-1 (IL-1), interleukin-23 (IL-23), or tumour necrosis factor-a (TNF-a) express E-selectin (CD62E), which enhances neutrophil adhesiveness even further. IL-1 and IL-23 also induce the production of the chemokine CXCL8 by endothelial cells, and this attracts still more neutrophils. TNF-a stimulates endothelial cells to secrete IL-1. It also promotes vasodilation, procoagulant activity, and thrombosis, and increases both expression of cell adherence proteins and the production of chemotactic molecules.
== Integrins ==
Many cell surface proteins make cells stock together, but the most important of these are the integrins. There are several families of integrins. Each consists of paired protein chains (heterodimers) using a unique a chain linked to a common β chain. For example, three B2-integrins are found on neutrophils. The a chain, called CD11a, b, or c, is linked to a common B2 chain (CD18). So these three integrins are called CD11a/CD18, CD11b/CD18, and CD11c/CD18. As described above, LFA-1 expressed by activated neutrophils binds to ICAM-1 expressed on capillary endothelial cells. CD11b/CD18 also binds leukocytes to endothelial cells and is a receptor for some components of the complement system (complement receptor 3 [CR3])
== Emigration ==
After binding to blood vessel walls and coming to a complete stop, the neutrophils emigrate into the surrounding tissues under the influence of chemoattractants. The migrating neutrophils squeeze between the endothelial cells and the basement membrane. This process has been called diapedesis or transmigration. They then crawl towards any invading microbes. Since neutrophils are the most mobile of all the blood leukocytes, they are the first cells to arrive at the damaged tissues.
== Changes in Endothelial Cells==
Bacterial products such as LPS, or alarmins from damaged tissues such as thrombin or histamine, cause capillary endothelial cells to express a glycoprotein called P-selectin (CD62P). P-selectin is normally stored in granules, but it moves to the endothelial cell surface within minutes after cell stimulation. Once expressed on the endothelial cell surface, the P-selectin binds to a protein called L-selectin (CD62L) on the surface of passing neutrophils. This binding is transient because the neutrophils readily shed their L-selectin. Nevertheless, the neutrophils gradually slow down and roll along the endothelial cell surface as they lose speed and eventually come to a complete stop.
== Changes in Neutrophils ==
As the neutrophils roll along the endothelial surface, the second stage of adhesion occurs. Platelet-activating factor secreted by the endothelial cells activates the rolling neutrophils so that they express a protein called CD11a/CD18 or LFA-1 (leukocyte function-associated antigen-1). LFA-1 is an adhesive protein or integrin, and it binds strongly to a glycoprotein called intracellular adhesion molecule-1 (ICAM-1 or CD54) expressed on the endothelial cells. This strong binding makes the neutrophil come to a complete stop and attaches it firmly to the vessel wall despite the shearing force of the blood flow. Adherent neutrophils also secrete small amounts of elastase. The elastase removes CD43 (leukosialin), an anti-adhesive protein, from the neutrophil surface, which allows the neutrophils to bind to the endothelial cells even more strongly. A third stage of increased leukocyte-endothelial cell adhesion takes several hours to develop and is mediated by cytokines and chemokines. Thus endothelial cells activated by interleukin-1 (IL-1), interleukin-23 (IL-23), or tumour necrosis factor-a (TNF-a) express E-selectin (CD62E), which enhances neutrophil adhesiveness even further. IL-1 and IL-23 also induce the production of the chemokine CXCL8 by endothelial cells, and this attracts still more neutrophils. TNF-a stimulates endothelial cells to secrete IL-1. It also promotes vasodilation, procoagulant activity, and thrombosis, and increases both expression of cell adherence proteins and the production of chemotactic molecules.
== Integrins ==
Many cell surface proteins make cells stock together, but the most important of these are the integrins. There are several families of integrins. Each consists of paired protein chains (heterodimers) using a unique a chain linked to a common β chain. For example, three B2-integrins are found on neutrophils. The a chain, called CD11a, b, or c, is linked to a common B2 chain (CD18). So these three integrins are called CD11a/CD18, CD11b/CD18, and CD11c/CD18. As described above, LFA-1 expressed by activated neutrophils binds to ICAM-1 expressed on capillary endothelial cells. CD11b/CD18 also binds leukocytes to endothelial cells and is a receptor for some components of the complement system (complement receptor 3 [CR3])
== Emigration ==
After binding to blood vessel walls and coming to a complete stop, the neutrophils emigrate into the surrounding tissues under the influence of chemoattractants. The migrating neutrophils squeeze between the endothelial cells and the basement membrane. This process has been called diapedesis or transmigration. They then crawl towards any invading microbes. Since neutrophils are the most mobile of all the blood leukocytes, they are the first cells to arrive at the damaged tissues.