Sterile Necrosis

00:01 Okay, that covers infection.

00:05 What about sterile necrosis? So sterile necrosis will also attract and recruit neutrophils, that's part of the early process in acute inflammation and then wound healing.

00:16 So there's no bugs in the sterile necrosis.

00:20 How are we getting them in there? Very pretty story, and actually kind of important to understand.

00:26 So in the tissues, we have macrophages.

00:30 And adjacent to the macrophage, we have some area of tissue necrosis, tissue injury.

00:38 That tissue necrosis will release, because the tissue, the cells are dead, will release danger signals.

00:47 Denature proteins, uric acid, ATP, for example.

00:52 So Danger-associated molecular patterns, DAMPs, as different than PAMPs, will be elaborated by the necrotic tissue.

00:58 And it's basically said, "We're dead." And here is evidence that we're dead.

01:03 And that's something that the macrophages can recognize as one of the major Sentinel cells.

01:09 And ATP is going to be one of the major things.

01:11 So as you see written underneath there, extracellular ATP will stimulate the macrophage to produce interleukin-1-beta.

01:20 At interleukin-1 now is going to be a major mediator.

01:23 So macrophages said, "Oh, there's dead stuff here." I saw the ATP. I'm going to make interleukin-1.

01:29 Interleukin-1 now drives the adhesion molecule expression on the endothelium.

01:35 That intercellular adhesion molecule-1 Okay, now we have a sticky endothelium that we can now recruit neutrophils to bind to.

01:44 So they're halfway there.

01:47 They know that there's something wrong because they're sticking to the endothelium.

01:55 We will also have the macrophages elaborate CXC chemokine.

02:00 Ah, CXC chemokine.

02:01 That's going to be important for recruiting neutrophils by changing the affinity of the integrins.

02:08 Terrific.

02:09 So interleukin 8 is an example of one of the chemokine there are many.

02:12 But now not only I have the leukocytes been rolling, the neutrophils been rolling, they are now firmly adherent to the endothelium in the vicinity of where this damage has happened.

02:23 What's the final chemoattractant signal that gets them to where they need to go? because there's no N-formylmethionine.

02:31 There is no cell wall from a bacteria? How do we get them to where they need to go to clean up the mess? That final step comes from the mitochondria in the dead cells.

02:42 And one of our earlier talks, it all comes back.

02:45 One of our earlier talks, we talked about the fact that mitochondrial proteins because mitochondria derived from prokaryotes, a long time ago.

02:54 Mitochondrial protein synthesis begins with N-formylmethionine.

03:00 Darn, that's exactly what it takes to recruit neutrophils to hit at bacteria, but this informal methionine on peptides is coming from the mitochondria.

03:12 And that's our final chemotactic gradient that gets the neutrophils to into the dead stuff, so that they can degrade it.

03:20 That's a beautiful example. Well, a long way to get there.

03:23 But the same pathways are happening in sterile necrosis too just slightly different signals.

03:30 Very cool.

03:31 Okay, so the neutrophils have arrived, yehey.

03:34 What are they going to do? Well, okay, they're going to eat, number one.

03:38 Number two, they are not just going to eat but they're going to kill and degrade whatever it is that they eat.

03:44 So if they are eating bacteria, or fungus, or other pathogens, they are going to kill it.

03:49 So they've eaten it, and they're going to kill it.

03:51 And they're going to elaborate mediators.

03:54 Those are the three stages that we have to kind of talk about next.