Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)"
From Biol557
Contents |
[edit] Abstract
- Neutrophils = polymorphonuclear leukocytes (PMNs).
- Neuts have to get across the endothelial wall of the vessel in order to get to a site of infection.
- Researchers are debating whether the neuts go between the endothelial cells (paracellular pathway) or through the cells proper (transcellular pathway).
- This article will review both views and attempt to reconcile the controversy.
[edit] Introduction
- Upon infection neutrophils become weakly attracted to the endothelial tissue.
- Neutrophils then roll along the endothelium with a saltatory stickiness.
- Once the neutrophils get to an area local to the inflammatory factors, they are "activated" and their adhesion to the endothelial cells is increased.
- At this point, we don't know whether the neutrophils go through or around the endothelial cells.
- The process of getting to the other side of the endothelium is called diapedesis (dia: through; ped: foot, child;).
[edit] Evidence in favor of paracellular diapedesis
- In vitro studies show that inflammatory molecules can cause endothelial cells to separate from each other.
- Induction of endothelial separation by PMNs seems to be possible but exaggerated in in vivo studies.
- PMN cells don't release elastase (a protease that has been shown to separate endothelial cells) which is supposed to be evidence that elastase is localized to the pseudopod that is wedging in between the endothelial cells.
- Adherins are proteins that are bound together to hold together the adheren junctions that hold endothelial cells together.
- Cadherins hold together the tight junctions that bind endothelial cells.
- Neutrophils have been shown to disrupt the interactions of adherins and cadherins.
[edit] Potential mechanisms involved in paracellular diapedes
- It may be that neutrophils can make proteases like elastase that can break down cadherins, adherins, and other proteins that hold the endothelial cells together.
- It could be that neutrophils communicate with endothelial cells to activate them to actively separate from each other.
- The evidence for this is that neutrophils drive up the Ca++ and beta-catenin levels in endothelial cells.
[edit] Evidence in favor of transcellular diapedesis
- There is some electron microscopy evidence that neutrophils use passages or pores that run through the cytoplasm of the endothelial cells in order to cross the endothelial border.
- This evidence is contested, however, because it is hard to be sure there were not junctions close by that were being used instead.
- Scanning electron microscopy has been used to show that the neutrophils take on a dumbell shape throughout the crossing process, indicating that the cell is squeezing through a small, circular pore.
[edit] Potential mechanisms involved in transcellular diapedesis
- It could be that pores are made in the endothelial cells, but this is unlikely because the membrane around the neutrophil (as it is migrating) seems to be plenty functional which is unlikely if it were taking part in the ultrastructure of making a pore.
- It is possible that a neutrophil could migrate through a fenastrae (are small pores in epithelial cells to allow for rapid exchange of molecules between blood vessels and surrounding tissue).
- Caveolae have been shown to generate membrane-lined tunnels that run all the way through endothelial cells and neutrophils have been shown to project finger-like processes where they are adhering to endothelial cells--two pieces of fact that could mean the neutrophils progress through these tubules to generate trancellular diapedesis.
- It has been shown that an advancing neutrophil pseudopod has the force necessary to pull the rest of the cell through a membrane pore or tunnel.
[edit] Summary
- In vivo neutrophils seem to prefer transcellular diapedesis and in vitro they seem to prefer paracellular diapedesis. Perhaps with further study we could reveal the difference in resistance that generates this discrepancy.
- In vitro, paracellular diapedesis occurs more readily at the interesection of three endothelial cells than at the intersection of only two. Moreover, in vitro endothelial junctions are less stable than in vivo endothelial junctions and therefore it is plausible that paracellular diapedesis is possible in vitro but not in vivo (thus driving neutrophils to undergo transcellular diapedesis in vivo).
- All this about in vivo versus in vitro however, is an oversimplification because there are examples of each type of diapedesis occurring in each situation.
- Therefore, there may be more to the argument than we think.
- It could be that the nature of the inflammatory response is a factor or the nature of the vascular bed.
- Hopefully more research will bring elucidation.
