Role of Interferon-γ (IFN-γ) in Chronic Inflammation

00:01 All right, we've been moving along through the various early stages of chronic inflammation.

00:08 We've moderated some of what the acute inflammation has been doing.

00:13 And now we're going to recruit in definitively the cleanup crew.

00:17 And the field marshals that will drive regeneration or scar.

00:22 And that's the macrophage.

00:24 Here's our roadmap.

00:27 So we previously moderated acute inflammation, we're not going to recruit macrophages.

00:31 And then we'll get on to the rest of the boxes on subsequent discussions.

00:37 Here's where we are in terms of our sequential peaks.

00:40 And again, we're at the green arrow.

00:42 So even as we are at the peak of the neutrophil response, and that arrow is about day one to two after the acute injury, that peak day one to two.

00:53 At that point, we're already starting the process for recruiting macrophages.

00:59 And that's where we'll be talking about is how we recruit them, and how we activate them and turn them on.

01:05 Okay, so that's where we are in our timeline.

01:09 Let's look at some histology.

01:11 So hopefully at this point, you'd be able to recognize this because we've seen this slide a couple times.

01:16 This is an acute myocardial infarct, a heart attack.

01:20 And it's one to two days out, because we have a lot of neutrophils that are percolating through.

01:26 And there's coagulative necrosis.

01:28 We have hypereosinophilic myocytes that are dead.

01:33 That's at one to two days, that's the peak.

01:35 But now we're going to start recruiting macrophages.

01:37 and by date three to five, we're kind of at the peak of macrophage recruitment.

01:43 So they're going to be cells that are in the interstitium that are more mononuclear.

01:48 They are very few neutrophils left.

01:50 The neutrophils have died, because they have a short lifespan.

01:54 And we're not recruiting anymore.

01:56 We're only recruiting at this point.

01:57 The endothelium is only recruiting macrophages.

02:01 And so they're crawling in.

02:03 At this point between where we were on the left hand side, where we are on the right hand side, there's also been a loss of the myocytes.

02:09 They have been eaten, they have been degraded by a combination of proteolysis.

02:15 And actually, the macrophages just kind of nibbling at the corpses.

02:18 Kind of gross, but that's what they're doing.

02:21 So we're now into a major zone of tissue breakdown, and predominantly macrophages, and that's peak day three to five.

02:30 Okay, how do we get them in there? In the process is actually very much like we labored over when we talked about acute inflammatory cell recruitment.

02:39 We have circulating monocytes wandering through the bloodstream, and then the endothelium becomes sticky.

02:47 It's the same process of rolling with selectins.

02:50 And then we're going to get firm adhesion using integrins.

02:54 So it's kind of the same process, different players.

02:58 And we're not going to get into those particular details here, but it's the same mechanism more or less in broad strokes, as what we had for acute inflammation.

03:07 So the monocyte becomes adherent.

03:09 And now crawls across the endothelium and into the tissue, where it becomes a macrophage.

03:18 Started as a monocyte becomes a tissue macrophage.

03:21 More magic happens at this point, and we're going to talk about that.

03:24 We have to activate it.

03:26 It's not enough for it to just be there, it actually needs to be turned on in interesting ways to have its next steps.

03:36 The recruitment process, as they say involves selectins and intergrins, just like we used for acute inflammation, with some differences.

03:47 The chemokines are different.

03:49 So remember, we talked about CXC chemokines, that recruit neutrophils? Well, it's CC chemokines, that are gonna be responsible for recruiting macrophages for the most part.

04:01 All right, as I say, we have to do something more to this macrophage other than just have it called into the extravascular space, we have to activate it.

04:11 There are various ways that this can happen.

04:13 We can have non-immune. So things like endotoxin, a component of bacterial cell walls, that's what endotoxin is.

04:22 Fibronectin, which is a component of the extracellular matrix that macrophages don't normally see, or other chemical mediators, such as some of the eicosanoids can potentially turn on macrophages.

04:36 And we'll talk more about what an activated macrophage is.

04:38 It's not just a word, there is actually activity that goes with that.

04:44 So you can have non-immune activation, You can also have clearly immune activation, and this is mainly coming from our PAL, the T helper 1 lymphocyte or the Th1 cell.

04:56 And that cell activated appropriately will make cytokines and in particular, interferon gamma.

05:05 This talk, this next part that we're going to talk about, there are a lot of factors.

05:10 There are many, many more than I am going to describe.

05:14 However, I'm going to give you kind of a framework for thinking about this.

05:19 And we will unfortunately have to talk about some factors specifically.

05:24 Keep in mind, these are important, probably the most important for each step.

05:29 But they are not the only factors that are involved.

05:34 So I've labeled these in quotation marks, "Factor 1", "Factor two", etc. They're not labeled like that.

05:41 If you look in any textbook, it won't say, Factor 1.

05:44 But factor one is going to be one of the first factors that we're going to talk about in this process.

05:49 And this is interferon gamma.

05:51 This is the cytokine that is one of the major activators of macrophages.

05:56 It's a pro-inflammatory cytokine.

05:59 So it drives macrophage activation.

06:01 It's synthesized by activated T helper 1 cells.

06:04 It's also made by cytotoxic T lymphocytes or killer T cells.

06:08 It's made by natural killer cells.

06:10 So a lot of different cells can make it.

06:13 But for the most part, again, as shown on the slide, there, always, always, always exceptions.

06:19 For the most part, think about Th1 helper T cells making interferon gamma, and this is going to be one of the immunologic drivers to activate macrophages.

06:30 Okay, so what does interferon gamma do? It actually has a whole bunch of functions besides activated macrophages.

06:36 It turns out that in the appropriate environment it inhibits viral replication. That's a good thing.

06:42 It drives the production of certain antibody isotypes.

06:45 So whether you make an IgG1, or an IgG4 as we'll talk about in subsequent talks, that's driven by interferon gamma.

06:56 It will drive T-cell differentiation.

06:59 So how well the T-cells get activated, and what they do is in fact pre-elected on being exposed to interferon gamma.

07:07 It will also activate natural killer cells and the cytotoxic T lymphocytes, and you're saying, "Wait a minute, those cells actually are secreting interferon, and it activates them too." Well, yeah, that actually happens the immune system a lot.

07:19 It's called autocrine stimulation. So don't worry about that.

07:23 It just there's actually a way to have a feed forward loop and get more, and more, and more activation.

07:28 And finally, in bold here, because it's the most important for this discussion.

07:33 interferon gamma drives macrophage activation.