Phagocytosis: Leukocyte Killing

by Richard Mitchell, MD, PhD

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    00:00 So, how do leukocytes kill? Well they phagocytized first.

    00:05 And they phagocytized because they have on their surface specific receptors.

    00:10 So you see a mannose receptor there, you see a scavenger receptor there are a variety of receptors that are able to bind motifs on the surface of our pathogen.

    00:19 And the pathogen here looks like Sputnik or Coronavirus.

    00:23 It's not a virus, it's a bacteria or a fungus.

    00:26 But there are specific motifs there that can bind two receptors.

    00:29 Once the receptors bind, then the membrane wraps up around them, kind of zips up around them.

    00:36 And we can internalize them in a phagosome, and then fuse lysosomes with them, and the lysosomes, and some of the things that are also recruited that time will break down the microbe.

    00:49 So perfect, we not only ingested them, but we digested them.

    00:53 Okay, there are specific receptors.

    00:55 So these are pattern recognition receptors, we talked about mannose receptor and scavenger receptor, all those things.

    01:01 Bound the antibody and complement will also work remember the obstinance, the things that make things tasty, and mannose-binding protein, for example.

    01:10 So these are all ways that we can specifically eat just the bad guys.

    01:15 So killing. It's not just a matter of dumping in lysosomal proteases, we actually have to do one extra step, to kill.

    01:23 And it's kind of cool because bacteria figured out how to evade this.

    01:26 I'll talk about that later.

    01:29 But any then, here we are, we are looking at the lysosomal protein primary granule.

    01:35 And there are a number of proteins that are present on the primary granule.

    01:38 These are within neutrophils.

    01:40 So we've ingested, but we haven't yet digested, killed, or digested the pathogen.

    01:47 So what do we do? So, we've now delivered the pathogen to our primary granule.

    01:52 It's basically a lysosome.

    01:56 On the surface of the lysosomes, there is, as you can see in that diamond a membrane oxidase.

    02:02 And once we have accumulated pathogens within the primary granule, we bring in from the cytoplasm, a cytoplasmic oxidase.

    02:11 So now we have a complex that will pump protons into the lumen.

    02:17 So this is an important step.

    02:19 Now, next step will require the incorporation of oxygen plus the protons to generate oxygen free radicals and in particular hydrogen peroxide.

    02:33 So this is going to be an important step on our way to killing.

    02:38 Next that hydrogen peroxide interacts with myeloperoxidase, which is another cell with another component of the membrane in these primary granules.

    02:50 And with chloride ions, we're going to generate from that hydrogen peroxide, the chloride and the myeloperoxidase hypochlorous acid, that's HOCl.

    02:59 See that? HOCl. And we'll know what that is? That is Clorox, that is bleach.

    03:06 So bleach works great on your toilet.

    03:09 It also works great inside your primary granules to kill bacteria.

    03:14 That's exactly we do the same thing.

    03:16 When we clean out our toilet bowls, we make hypochlorous acid do the work to kill the cells and it's through free radical damage.

    03:23 So we have free radicals from the superoxide from the hydrogen peroxide, from the hydroxide free radicals and importantly hypochlorous acid or bleach, and that kills bacteria.

    03:35 And then now that we killed them proteases will be able to degrade them.

    03:40 This uptake of oxygen to make the oxygen free radicals is called an oxidative burst.

    03:47 So there will be a massive kind of uptake of oxygen utilization of oxygen, which we can measure oxidative burst.

    03:54 The reactive oxygen species that get generated that are shown there on the box will then be responsible for killing the bacteria.

    04:02 And finally lysosomal proteases will degrade them.

    04:05 So we've ingested, killed, and digested.

    04:10 A very cool process.

    04:15 Another thing that we've just learned recently, about neutrophils is that they also extrude their intracellular contents into the extracellular space as a way to corral and kill microbes outside of them.

    04:31 So they don't have just eat, but they can in fact kill by extruding their material.

    04:36 So this is called a neutrophil cytoplasmic net.

    04:41 So, or neutrophil extracytoplasmic net, or NET.

    04:47 Contained within that is going to be DNA as shown here.

    04:51 Then we're going to have histones as part of the DNA structure.

    04:54 We're going to have myeloperoxidase.

    04:56 Oh wow, we can even form potentially hypochlorous acid out there.

    05:01 There are elastases.

    05:02 There are cathepsin and there a whole variety of things that are part of the net that it's very sticky, and it goes out and sits out in the space and can capture up microbes.

    05:13 And then we can kill them in that location.

    05:16 So this is an X neutrophil extracellular trap or a NET.

    05:23 It's a mechanism for neutrophils that have extracellular release and killing.

    05:29 It includes histones and DNA.

    05:33 There are a lot of attached granules that can also be potentially cytotoxic.

    05:37 It's a questers and kills bacteria fungus and viruses.

    05:41 And the cell dies when it does this.

    05:44 So the neutrophil by extruding it's kind of guts into the space around it will die.

    05:50 It's a distinct process from apoptosis which neutrophils will also undergo after a short period of time.

    About the Lecture

    The lecture Phagocytosis: Leukocyte Killing by Richard Mitchell, MD, PhD is from the course Acute and Chronic Inflammation.

    Included Quiz Questions

    1. Bound complement
    2. T-cell receptors
    3. Neutrophil extracellular trap
    4. Interferon-alpha
    5. Phosphatidylinositol
    1. Myeloperoxidase
    2. Metalloproteinase
    3. Glutathione reductase
    4. Glucose-6-phosphate dehydrogenase
    5. NADPH reductase
    1. They have attached granules that release proteases.
    2. They result in neutrophil death through apoptosis or necrosis.
    3. They are primarily composed of collagen fibers.
    4. Their nuclear membranes remain intact during the process.
    5. They are caused by faulty over-activation of the lysosomal enzymes.

    Author of lecture Phagocytosis: Leukocyte Killing

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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