Walzog's "Adhesion molecules: the path to a new understanding of acute inflammation" (2000)
From Biol557
[edit] Abstract
- 100 years after we defined inflammation, we've discovered the molecular mechanisms by which it works.*Extravasation: "the process of exuding or passing out of a vessel into surrounding tissues; said of blood or lymph or urine."
- We've discovered that the specificity of the adhesion molecules involved in getting the neutrophils through the vessel wall are responsible for the way leukocytes are recruited and activated in an inflammatory response.
[edit] Introduction
- Elie Metchnikoff defined inflammation as "a reactionf of phagocytes against a harmful agent" and otherwise laid down the foundations of immunology.*"This review focuses on the importance of adhesion molecules in the control of acute inflammation, which is characterized by immediate infiltration of polymorphonuclear neutrophils (PMN) at sites of lesion, followed by monocytes and eventually lymphocytes."
[edit] How are leukocytes made to leave the circulation? The multistep paradigm of leukocyte recruitment
- Research has shown that leukocyte diapedesis depends on both the leukocytes and on the endothelial cells of the vessel wall.
- Getting leukocytes to the site of infection from the blood stream "involves margination and capturing of free-flowing leukocytes, leukocyte rolling, activation, firm adhesion, and spreading, transendothelial diapedesis, and chemotactic migration of the leukocytes."
- Before any of this can happen, the endothelial monolayer must be activated by tissue-derived signals such that the endothelial cell will express adhesion molecules and secrete inflammatory mediator molecules.
- Because leukocytes are some of the largest cells in the blood stream, they flow through the axis of the vessel. They must get near to the vessel wall to induce the initial adhesion to endothelial cells.
- Once they initially adhere, they continue to move through a rolling motion along the endothelial surface.
- Because the leukocytes are now near enough to the endothelial layer, the inflammatory mediators have an effect and the leukocytes will bind more tightly.
- Once they are firmly bound to the endothelial cells, leukocytes go through diapedesis (see Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)).
- Once across the endothelial wall of the vessel, the leukocytes are drawn toward the infection or injury via chemotaxis.
- The response to infection, in terms of spacial and temporal organization of responding cells, can be varied based on which cells are recruited (neutrophils, monocytes, etc.), the inflammatory stimulus, the tissue, and the context of activation including adhesion molecules and inflammatory mediators expressed.
[edit] How do leukocytes penetrate tissue in a targeted fashion? A pivotal role for adhesion molecules
- "... adhesion molecules allow the interaction of free-flowing leukocytes with the vessel wall and all subsequent adhesive interactions that are required for emigration into the tissue."
- Adhesion molecule expression choice helps determine where leukocytes will end up and helps coordinate an effective, killing response.
- Adhesion molecules include selectins, integrins, immunoglobulins, and other molecules.
- Adhesion molecules are expressed on the surface of cells and act to bind to other adhesion molecules or to elements of the extracellular matrix in order to promote cellular movement or anchoring.
- Selectins, which are expressed on leukocytes, are crucial to the capturing and rolling of leukocytes against endothelial cells of the vessel.
- Integrins, which are expressed on leukocytes, monocytes, and lymphocytes, facilitate the firm binding of leukocytes to endothelial cells by binding the immunoglobulins expressed on endothelial cell surfaces and facilitate the extravasation of monocytes and lymphocytes.
- Immunoglobulins, which are expressed on endothelial cells, are important for tight binding of leukocytes.
- Cadherins, which are expressed on endothelial cells, seems to be associated with transendothelial migration of leukocytes.
[edit] How is the inflammatory cascade initiated? Insights from the molecular mechanisms of leukocytes-endothelial cell interactions
- The whole process of recruiting leukocytes and such to respond to injury starts with the secretion of soluble molecules like histamine, IL-1, and TNF-alpha by tissue macrophages, mast cells, and fibrocytes.
- These factors cause the endothelial cells of nearby vessels to express adhesion molecules and to secrete inflammation mediators into the blood stream (see previous paragraph about factors that cause leukocytes in the blood stream to begin to adhere to the endothelium near the site of injury).
- "The diversity and specificity of the adhesion molecules expressed constitute the molecular basis for the site-directed traveling of leukocytes during inflammation (2)." That is, the adhesion molecules expressed determine what the leukocytes will do: keep rolling, bind tightly, go through diapedesis, etc.
- "Subsequent to firm adhesion and transendothelial migration, the leukocytes are recruited chemotactically to their target regions by a variety of soluble mediators."
- "Chemoattractants exert their effects by binding to specific receptors on the leukocyte surface ... that are heptahelical molecules with seven transmembrane domains that activate intracellular signal transduction cascades via ... G proteins.... Some of these receptors, including that for interleukin 8, show promiscuous ligand binding by exerting affinity to other structurally related chemoattractants,...."
[edit] How is the activation of PMN controlled and prevented from exploding? Development of weaponry and mechanisms of containment
- Adhesion molecules don't just function as migratory signals, but also help to induce signals into the cell and can themselves regulate cellular pathways in leukocytes, thus providing a way to turn on a site-of-injury specific cellular process.
- "Thus integrins as well as other adhesion molecules integrate ligand-dependent, i.e., site-specific, and signaling functions at the molecular level."
[edit] How is the process of repair and tissue remodeling initiated? Toward a new definition of inflammation
- There is growing evidence that inflammation is not just an immune function, but also a critical part of regeneration and repair.
- Patients deficient of adhesion molecules show not only reduced ability to fight infection but also reduced ability to repair and restructure tissue.
- "The present evidence that the inflammatory response does not end with the elimination of foreign particles may imply the requirement of a novel definition of inflammation."
- "However, the biological significance of these findings remains to be proven...."
