Different Macrophage Populations

00:01 Okay, so we start with our monocyte, that has crawled out into the tissue, and it's a macrophage now.

00:08 And we're gonna stimulate it a couple different ways, you can already see there's a left hand side, and there's a right hand side.

00:13 That's because macrophage populations are not purely just one population.

00:19 They're probably up to three or four that we're aware of now, but I'm not going to get into all those details.

00:24 I'm gonna keep it relatively straightforward.

00:26 There are two flavors that I'm going to talk about.

00:30 And certain microbial stimuli through the toll-like receptor, or interferon gamma, which is the main one that we just talked about factor 1 is going to stimulate the monocyte and have it turned into a classically activated macrophage.

00:47 Designated as an M1, okay.

00:50 Clearly on the other side, not yet showing there's going to be M2s.

00:53 Let's focus on M1s for right now.

00:55 So driven by these microbial factors, or driven by interferon gamma, we get a classically activated macrophage.

01:04 That classically activated macrophage is a lean, mean fighting machine.

01:08 This is a very pro-inflammatory phenotype.

01:11 It's going to make a lot of ROS, Reactive Oxygen Species.

01:14 It's going to make nitric oxide, which is also toxic to bugs, to pathogens, but also us.

01:20 It's going to make a lot more lysosomal enzymes.

01:23 So this cell is bigger, more robust, and making a lot of mediators that are going to help definitively clean up the area of injury.

01:35 These have a number, the things that are made by the classically activated macrophage, the M1 macrophage, have a lot of microbicidal actions.

01:43 They will kill pathogens.

01:45 They also are much better at eating phagocytosis.

01:49 And they're much better at killing.

01:50 So overall, as I said, a lean mean fighting machine.

01:55 They will also make pro-inflammatory cytokines.

01:59 Interleukin-1, Interleukin-12, Interleukin-23, these are going to be cytokines that are going to be really important for recruiting additional macrophages, and driving the entire environment of the host in that location to be very aggressive, to clear out infection.

02:18 So the classically activated macrophage is intended to clean up, and sterilize, help finally sterilize the wound, the area of injury.

02:28 And this is all going to lead to a lot of killing and a lot of pathologic inflammation.

02:33 So you can see these guys have the capacity to do some significant damage, both against pathogens and against local tissues.

02:43 On the right hand side, if we stimulate that monocyte, that's crawled out and become a macrophage in the tissue with interleukin-13, or interleukin-4.

02:52 There are other things that can do this too.

02:54 But interleukin-13, and interleukin-4, we will get the alternatively activated macrophage.

02:59 So the M2 macrophage.

03:02 Kind of looks the same, if we look down the microscope, they look the same, but they have very different activities.

03:08 So the M2 macrophage, is going to be making a variety of different kinds of cytokines that are actually anti-inflammatory.

03:16 So that interleukin 10, the transforming growth factor beta, all these additional factors are going to be anti-inflammatory.

03:24 So this is a way that we're modulating the local effects of those lean mean fighting machines with a kinder, gentler macrophage.

03:34 That empty macrophages also not only turning off inflammation, but it's also going to be making factors such as TGF-beta, and arginase, and other things that are going to be important for wound repair and fibrosis.

03:49 So this is why the macrophage in general, starting from that monocyte, that crawled out was a macrophage, depending on it gets stimulated, it can be pro-inflammatory, or if it's stimulated a different way, it can be now the field marshal to provide the direction for wound healing.

04:08 So in the same population, we cannot tell them apart, but there may be mixtures of M1 and M2, and probably early in the process, day three to five, it's mostly M1s.

04:20 But as we get further out in the process, a week or two weeks or more, we're probably more M2s.

04:26 So just kind of think of them as sequential.

04:29 There's a couple more things about this.

04:32 So it turns out that all those signals that drive M1 activation also turn off M2 activation.

04:40 And conversely, things that drive M2 activation will turn off M1.

04:44 So there is a big network of regulatory activity going on here.

04:50 Don't get too bogged down the details, but in your mind, realize that this is just an example.

04:55 Another good example of that paradigm where every pro, has an anti.

04:59 And so as we're making pro-inflammatory things, we're making anti-inflammatory things and they're regulating in each other all the time.

05:06 And it turns out that the anti-inflammatory effects at the bottom interleukin-10, and TGF-beta, are going to turn off pathologic inflammation.

05:15 So those are going to be some important factors.

05:17 We'll come back to many of these in subsequent slides.

05:20 But just keep in mind, we have two flavors of macrophages.

05:24 Two basic flavors.