Mast cell mediator release mechanisms

There are many ways for mast cells to be activated.  Each of them involves a sequence of events involving several molecules.  These molecules change the next molecule in line in a way that causes it to perform a specific action.  It is hard to visualize and one of the harder concepts to understand about molecular biology.

I think of it like carrying the Olympic Torch to the Olympic Games. Before the Olympic Games, the Olympic Torch is lit in Greece.  Then a series of different people from all over the world carry the torch part of the way before giving it to another person.  Many, many people are involved, and the environment changes, but the torch always stays lit.  Finally, the very last person carries the torch into the stadium to light the Olympic Flame to open the Olympics.  Even though the people and environment changed, it’s still the same flame.

In the body, pathways are just like passing this Olympic torch. Instead of people carrying the flame and keeping it lit, molecules carry a message that they tell to the next molecule, and so on until the pathway ends.  The best known mast cell activation pathway is IgE activation.  IgE binds to a receptor on the outside of the mast cell.  The receptor knows that this means it has to degranulate.  It passes this message to a molecule, which passes the message down the line, just like the torch, until the mast cell degranulates.

Mast cells are well known for having many large granules that hold mediators until there is a signal to release. Granules are like pockets and mast cells stuff them full of premade mediators like histamine and tryptase. Mast cells actually sort mediators so that the granules are organized and mediators aren’t distributed randomly. The way mediators are stored together greatly affects the action of these molecules once they are released.

Large scale degranulation (sometimes called complete or anaphylactic degranulation) is the best known mast cell mediator release mechanism. In this kind of degranulation, granules swell and then lots of granules actually clump together to make a very large pocket. Then, this super pocket goes to the edge of the mast cell, the cell membrane, and pokes a hole to the outside.  The mediators in the super pocket are then released at once.  The granules and membrane have holes in them that will eventually be repaired. Following large scale degranulation, it takes about two days for normal mast cells to regranulate.

There is another kind of degranulation called piecemeal degranulation. This involves release of some mediators in a granule.  There is still a lot we don’t know about this process, but the general idea is that a regular granule puts some of its mediators into a tiny little bubble.  The little bubble then goes to the edge of the mast cell and slowly releases these mediators.  In piecemeal degranulation, the granules do not clump together to make one large granule, and there is no hole made in the membrane.  It is believed that some molecules help to push the mediators out of the cell but we don’t know what they are.

A number of mast cell mediators are not stored in granules and are instead made upon signals from specific pathways. Because these molecules aren’t stored in granules, it takes some time for them to be produced and released after mast cell activation. Lipid mediators, like prostaglandins and leukotrienes, are packed together and then transported across the membrane to the outside by other molecules.  Cytokines and chemokines are also produced on demand and then stored in small bubbles.  These small bubbles are then actively pushed out of the cell in a process called exocytosis.

References:

Moon TC, et al. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol 2014: 5:569.

Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol 2014: 14(7), 478-494.

 

5 Responses

  1. Chris June 23, 2016 / 11:44 pm

    I am recently diagnosed with MCAD due to all of my symptoms and elevated prostaglandin levels. I have not been able to get on any medications to help my symptoms. Every single medication increases my flushing, which has become an almost constant symptom although there are plenty of times when I have no flushing at all. If I continue to take the medications will the flushing that I know is caused by the medication subside? Antihistamines and NSAIDs (including celebrex) all increase my flushing and dermographism to an undesirable level. Thanks for listening!

  2. Mark June 24, 2016 / 4:28 am

    >”There are many ways for mast cells to be activated.”

    Indeed. And as you further aptly underscore, much remains to be investigated, documented published. The 2 scenarios you do describe don’t, or likely don’t, encompass all mast cell mediator synthesis, release. As I imagine you realize, don’t dispute. I could describe a couple others while barely touching the tip of a proverbial iceberg. Except, it’s hard to soundly grasp where data, evidence leave off and surmise/theories kick in.

    • Lisa Klimas June 24, 2016 / 2:31 pm

      I described four here, I just wasn’t detailed in exocytosis and active lipid transport. As far as we know, there are only two other release mechanisms and they are similar to what is described here.

  3. Kathy June 24, 2016 / 11:41 am

    Lisa,
    This is the best explanation of how mast cell mediators degranulate I’ve ever read!!! Does this also explain why some of us MCAS folks are so called “leakers” as opposed to “shockers”? Or are we all leaking until we have a massive degranulation when something pushes us over the edge?
    Thanks so much for taking the time and effort to educate us about this very complicated and crappy disease.
    Kathy

  4. Joan June 24, 2016 / 12:26 pm

    Do you know where heparin fits into the degranulation process and what triggers it’s release?

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