To Scratch or Not to Scratch, That Is the Question

Summary

Podcast Summary: Derms on Drugs

Episode: To Scratch or Not to Scratch, That Is the Question
Date: March 14, 2025
Hosts: Matt Zirwas, Laura Ferris, Tim Patton
Guest: Dr. Dan Kaplan (University of Pittsburgh)

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Brief Overview

In this lively and insightful episode, the Derms on Drugs team dives deep into the science of itch and scratching—a topic at the very heart of dermatology but, as they show, still full of surprises. They welcome special guest Dr. Dan Kaplan, whose recent paper in Science uncovers new neurological and immunological underpinnings in the infamous itch-scratch cycle. Together, the panel explores why scratching feels so good, how scratching may drive both inflammation and evolutionary advantages, and what this means for conditions like atopic dermatitis. As always, there's plenty of high-level banter and a dash of the show’s signature humor.

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Key Discussion Points & Insights

1. The Pleasurability of Scratching (00:13–04:43)

• Matt reviews a landmark fMRI study by Gil Yosipovitch showing that scratching an itch activates brain reward circuits similar to those triggered by sex, gambling, and drugs.
  • Only active scratching of one’s own itch (not having someone else do it, or scratching non-itchy skin) produces this intense pleasure.
  • Quote: “Active scratching… activates the same parts of your brain as having sex, gambling, using drugs, all these addictive behaviors.” (A, 01:35)
  • The panel debates evolutionary reasons for this: is intensive itch relief fundamentally valuable for survival?

2. The Evolutionary Purpose of Itching and Scratching (04:43–06:46)

• Discussion on whether scratching’s main role is to remove parasites (fleas, mites, lice) or something deeper.
  • Insight: Scratching may have evolved as a mechanism to get rid of dangerous skin-dwelling parasites, with scabies given as a modern example.
  • Quote: “The scratching really does have a benefit to removing mites… scabies. But it’s probably the same for body lice.” (C, 05:44)

3. The Itch-Scratch Cycle and Keratinocyte-Mast Cell Crosstalk (06:53–14:43)

• Tim presents a 2025 JID study on how mechanical stretching of keratinocytes (from scratching) produces reactive oxygen species (ROS), activating mast cells (via TRPA1), releasing tryptase, and further driving itch.
  • Summary of experiments: Stretching keratinocytes leads to ROS, which prompts mast cells to degranulate—a core of the itch-scratch cycle in conditions like atopic dermatitis.
  • N-acetylcysteine (NAC), an antioxidant, can inhibit this process—aligns with its clinical utility for some skin picking disorders.
  • Quote: “The takeaway was—the takeaway. Stretched… keratinocyte supernatant… appeared [to] upregulate TRPA1 expression on mast cells, leading to the release of tryptase…” (D, 08:42)
  • Dr. Kaplan highlights the complexity of keratinocyte-derived factors (TSLP, IL-33, ROS), all of which can directly or indirectly worsen itch/inflammation.
  • Matt notes this evidence finally made him “buy into” the itch-scratch cycle as a real, propagating force in disease.

4. The Role of Mechanical Stretching in Disease Localization (13:58–15:11)

• Team discusses why psoriasis and atopic dermatitis localize to areas of high skin stretching (elbows, knees).
  • Could mechanical stress itself be pro-inflammatory?

5. Neuro-Immune Interactions: Itch, Pain Neurons & Mast Cells (15:33–24:29)

• Dr. Kaplan explains research into how sensory neurons in the skin interact with immune/inflammatory responses.
  • Pain-sensing neurons (expressing TRPV1, capsaicin receptor) are key in general inflammation, while itch-specific neurons may be crucial in allergic responses.
  • Key Mechanism: Mast cell activation isn’t just via IgE; there’s also the Mrgprx2 receptor. This receptor can be triggered by neuropeptides like substance P (released by neurons), microbial products, and more.
  • Quote: “Mast cells released a lot of histamine. But if you look… inside the granules, there’s like, you know, a witch’s brew of different proteases and inflammatory amines… all kinds of things.” (C, 17:17)
  • Activation synergy: Simultaneous activation via IgE and Mrgprx2 leads to maximal degranulation/inflammation.
  • A pivotal experiment showed that mice unable to scratch (wearing Elizabethan collars) don’t get inflammation even with itch neurons present—implying it’s the act of scratching, not just itch, that triggers the immune cascade.

6. Scratching: Evolutionary Harm and Benefit, Clinical Implications (24:29–30:55)

• Scratching can clearly exacerbate inflammation—explaining chronicity in eczema.
• However, scratching may also protect by reducing bacterial overgrowth (e.g., Staph aureus) as shown in mouse models.
  • Quote: “Scratching, while being detrimental, if you have an allergic situation like eczema, is actually beneficial… because it helps reduce the amount of Staph on our skin.” (C, 29:06)
• Debate over whether completely eradicating itch/scratch would harm us—consensus: probably only acutely, e.g., with scabies.

7. Future Therapies and Unanswered Questions (26:51–27:27, 30:25–30:57)

• Multiple companies are developing drugs that block the Mrgprx2 pathway, possibly effective in urticaria or atopic dermatitis.
• The discussion surfaces open questions about which mast cell degranulation pathways drive which diseases, and whether blocking itch could have unintended downsides.

8. Memorable Quotes & Humor

• On study complexity:
  “You needed a PhD to fully understand everything. …This is all Cyrus’s fault. He was like, hey, you should do this paper… it was like 47 pages of stuff.” (D, 08:03)
• Matt, after changing his mind:
  “And son of a bitch, it turns out I was wrong.” (A, 13:43)
• Kaplan, on mast cell granules:
  “There’s like, you know, a witch’s brew of different proteases and inflammatory amines.” (C, 17:17)

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Important Timestamps

| Time | Topic/Quote/Event | |----------|-----------------------------------------------------------------------| | 00:13 | Intro & setup—scratching as pleasure/reward | | 03:19 | Discussion of “active scratching” vs. “passive scratching” | | 06:53 | Patton presents keratinocyte/mast cell-ROS paper | | 10:14 | Kaplan deepens: keratinocyte-derived itch factors | | 11:24 | Matt: This paper finally validates the itch-scratch cycle | | 15:33 | Kaplan explains neuro-immune crosstalk; mast cell biology | | 20:04 | Kaplan: Mouse experiments reveal scratching (not neurons) drive inflammation | | 24:29 | Discussion of scratching as an evolutionary tool (& clinical harm) | | 29:06 | Scratching reduces Staph skin colonization (mice), potential benefit | | 30:25 | Ferris: Does itch/scratch drive bullous pemphigoid? | | 33:13 | Trivia segment on "itch" pop culture (Seven-Year Itch, Cat Scratch Fever) |

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Notable Moments & Quotes with Attribution

• Kaplan on synergistic mast cell activation:
  “If you activate both [IgE and Mrgprx2] pathways at the same time, you get this big synergistic response and that’s what’s required for the inflammation.” (C, 23:15)

• Ferris, on reducing itch:
  “Do you think there’s any sort of potential harm of, you know, if you could completely knock out itching, do you think that would hurt us?” (B, 30:30)

• Patton’s meta-commentary:
  “You really need to make, like, ‘If You Give a Mouse a Cookie,’ but with your research… with little cartoon drawings, and, like, I would have understood this much, much better.” (D, 32:15)

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Conclusion

The panel concludes that while scratching can clearly worsen inflammatory disease and drive chronicity (notably in eczema), it may carry surprising short-term antimicrobial benefits—explaining its potent evolutionary reward and persistence as a human behavior. Dr. Kaplan’s research illuminates new cellular pathways (especially the dual-trigger mast cell degranulation) that offer hope for future targeted therapies. The episode blends high-level derma-science with the team’s signature wit, making even immune crosstalk lively and accessible.

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For more topics or to submit questions:
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Next episode drops next Friday!

Transcript

[A]

Welcome to Derms on Drugs, a video podcast brought to you by scholars in medicine. Derms on Drugs is where cutting edge derm meets so so comedy. I'm Matt Ziers, and each week I'm joined by my residency buddies, Laura Faris and Tim Patton. We use our 60 years of combined derm experience to discuss, debate and dissect the hottest topics in dermatology. It's everything you need to know to be on the cutting edge of derm, and it'll be the most fun you've ever had while actually learning something useful. New episodes drop every Friday, so make sure you set your calendar. And boy, do we have some cool stuff this week. So over the last, for those of you who are not like itch, you know, live and die, love the itch research world. We've had some of the most fundamental questions in the history of dermatology answered in the last couple of months here, and I am so excited to have Dan Kaplan from the University of Pittsburgh on to talk about his article on scratching and itching, which was published in Science. Science, for God's sake. That's like as real as a journal gets. I personally am convinced that it is the first time that an article about scratching has ever been in science, but I didn't look that up to confirm it. But so let's just go ahead and jump right into it and I'm going to start just with an article that I think is fun and it's been around for a long time. So this was a study out of roughly 10 years ago done by Gil Yasipovich, the godfather of itch. And what so it's brain's reward circuits mediate its relief. A functional MRI study of active scratching. And basically, here's what Gil did. He put people in an MRI machine and then induced. So first just scratched like an area on their forearm and then induced itching using cow hage, which is itch powder. And then either an investigator scratched it or the person scratched it. And so the investigator scratching it is passive scratching. The person scratching it is active scratching. And he looked at what parts of your brain lit up. And the main takeaway from this was that itch relief. Active scratching, an itch activates the same parts of your brain as having sex, gambling, using drugs, all these addictive behaviors. And so there is a strike. What he proved was that there's a strong pleasurability aspect to itching. And that has always fascinated me because of the idea that like, why did evolution make, why was it so valuable that evolution put it on the same level as getting sugary foods, fatty foods, you know, whatever. And we really never had a good answer to that. And I think the papers we're going to talk about today start to give us some of that answer.

[B]

Was only scratching the. When it was only if you did the scratching and you were actually itchy. So it's not the scratching, it's the quelling, the itch, that is what creates that pleasure circuit. Is that right?

[A]

Yes, so it was. That's exactly right. And, and interestingly, because it is an interesting question of what feels better, you know, you scratching an itch, your own itch, or somebody scratching it for you, and this really looked like it was somebody scratching it for you. Because that's an interesting question. If you think about, like, an itchy spot on your back, like how good it feels whenever somebody hits the right.

[C]

Spot, but they never do.

[A]

That's exactly right.

[C]

They never hit that spot.

[A]

That was actually part of this article because part of me wondered is it did. Did the. Did other people scratching it feel better just because they got it, just because. Not feel as good because they just didn't quite get it right? They weren't in the right spot, the right, you know, strength. And it, it turned out that whenever you scratch your own itch, it actively. It activates different parts of your brain than if somebody else scratches your itch. So there is a fundamental difference. Just, you know, it's fascinating. I never knew what to make of it, but it was just fascinating. Patton, you got anything you want to say about this one?

[D]

No, I think we talked about this. I think that, you know, you, you. We scratched to get off our skin. That was going to be bad for us. And I know you talk about mosquito bites and that doesn't happen until later and how ticks don't itch. But if you think about a flea infestation or louse or mites or lice, you got to get that shit off you or it's going to probably give you some bad disease. So that always meant I was happy with that explanation. I'm not saying that these other explanations are wrong. I was good with that one.

[C]

Okay.

[A]

I still say, man, that by the time it's itchy, the bug is gone from the spot. That was.

[D]

If you think about fleas in general, though, right? You're, you're, you're. We're prehistoric little mammals. We're covered in fleas. And, like, they start biting you and you start to get itchy, but they're still on you. And so you Just gotta scratch em off.

[A]

But they're not in the. They're not in the spot that's itching. If like right here, isn't it?

[D]

What's that?

[A]

It doesn't yesterday, right.

[C]

Because it takes a month to get the adaptive response right to fleas. And like scabies takes about a month right before you start to get itchy. If you think about people who can't scratch, like in a nursing home or something, they get Norwegian scabies. Right. So the scratching really does have. Have a benefit to removing mites scabies. But it's probably the same for body mice.

[A]

Damn it, Dan, you're. It's hard for me.

[B]

No more smart people on our. We don't sign.

[A]

I don't have an answer to you, Dan. Yeah, trying to convince me for a week and I'm like, nope, nope, nope. You got me with right there. No Regents gabies. And they in nursing home patients.

[C]

All right, but in the case of like ticks or mosquitoes, you'd argue that. Well, they've evolved to actually avoid the immediate.

[D]

I was going to say the same thing. Otherwise.

[C]

Otherwise they'll be taken out.

[D]

I think maybe that's why ticks evolved to like. There were probably ticks that did induce that itch right away, but you start scratching them off and, you know, maybe it got rid of it.

[A]

All right, let's move on to our next article here. So, Dr. Patton, what do you got?

[D]

Well, I did this one from January 2025 JID entitled Epidermal Mechanical Scratching Induced ROS. So reactive oxygen species exacerbates the IPS scratch cycle via TRPA1 activation on mast cells in atopic dermatitis by HuT Al or WHO et al a long title, but that's really the takeaway. You scratch keratinocytes make reactive oxygen species ROS activate mast cells via TRPA1. Mast cells release all their things and you get more itchy. And so they did it with a bunch of experiments. I don't. You know, the first experiment, they stretched these. These keratinocyte cell lines and that made keratinocytes release reactive oxygen species that was suppressed by N acetylcysteine. Second experiment, they irritated mouse skin with a chemical and tape stripping. And they showed that you have increased mast cells and tryptase in the dermis tape stripping, which did, you know, higher levels of both. They took this mast cell line. They showed if you stretch the keratinocytes, you take the supernatant, you add it to a matrix thingy that they made with the LAD2 cells which are this mast. It makes these mast cells release Tryptase similar to if you just exposed LAD2 cells to H2O2. They did gene regulations 945 genes upregulated, 654 genes downregulated. I think we should go through each one of these for completeness sake. No, they did cluster analysis on those genes and the summary from the gene studies was upregulation seen in genes involved in mast cell activation, type 2 inflammation, redox processes, ion channels. I don't, you know, there were four other experiments. I don't really feel like going all through the whole things. This is all Cyrus's fault. He was like, hey, you should do this paper. And I was like, yeah. And then I went to print it out and it was like 47 pages of stuff. It was really hard. You needed a PhD to fully understand everything. But the takeaway. Yeah, the takeaway was the takeaway. Stretched hat, cat supernatant appeared, TRP A1 expression on mast cells that led to the release of Tryptase. And you know, so that's why we itch. And it also had these other pro inflammatory cytokines, you know, I'm guessing, Dan, you understood this paper way better than I did. What were your takeaways?

[C]

I thought it was a really interesting paper. I guess it's not out yet, so I'm glad you sent it to me. I like reading papers in the. The gi.

[D]

We're on the cutting edge on the show.

[C]

Always. Always. And so what it does is it adds to the list of things that keratinocytes that release. Things that keratinocytes can release that are itchy. Right. So when you scratch the skin, you release one cytokine called tslp. It's very well characterized and it's very, you know, it can activate mast cells and other cells as well. Right. And can be important in triggering itch. And IL33 is another example of things that can be released. So it's a really nice paper to just to add to the list of the complex stuff, I'll use the word stuff that is released by keratinocytes that can have biological effects on mast cells and on many other cells in the skin as well. So I thought it was really, really, really interesting for that reason.

[A]

My takeaway from it was that they made this gel and put keratinocytes in it. And then they went basically and showed that moving the keratinocytes, like deforming them just a little bit, generated these reactive oxygen species. That then activated mast cells and the whole thing. Because I've always had a big problem with the itch scratch cycle. Like people like to talk about the itch scratch cycle. And this finally made me buy into it. And the reason I never really bought into it was that if it was just that the scratching is mechanically damaging the skin surface, then in all of our atopic patients it ought to be that we can see manifestations of scratching everywhere, that they've got a rash and you can't. The majority of places where they've got a rash, there's no evidence of scratching. So I've always been like, ah, that's baloney. But this is some of the first stuff in dance paper as well that really says to me, scratching itself might have a way that it's generating inflammation.

[C]

Yeah. A good example.

[A]

Go ahead, Dan.

[C]

Is people who are dermatographic. Right. That's a perfect example of it. Where now you've got mast cells that are not fully activated, but they sort of have this heightened reactivity. And now if you scratch the skin, the stimuli from scratching is sufficient to push those mast cells over the edge, degranulate, and you get, you know, you get urticaria wherever the scratching has occurred.

[B]

That's interesting. So, yeah, so it's really, and it's not like you're scratching and excoriating, it's really just the pressure of the scratching and it's, yeah. So I like the idea from this paper that it's like the mechanical stretching of the keratinocyte. That's the signal. The other thing I thought was interesting is that N acetylcysteine inhibited this. And we know that there's some data that N acetylcysteine can also be helpful in like skin picking disorders. Right. So maybe it sort of squelches the reactive oxygen species and the, you know, downstream effects. I don't know. I mean, I, I, I always kind of wondered, why does N acetylcysteine work? Do you think it fits into this mechanism or do you think it. Not really.

[D]

That was the last experiments they did were, yeah, let's, let's welch or whatever, gather up these reactive oxygen species. With N acetylcysteine, they also had a medication that blocked that TRPA one. I think it's like a channel on the mast cells. And so were both of those, you know, and doing them combined was better than each one on its own. And so, you know, potential therapeutic for itchy stuff is the TRPA1 blocker along with something that sort of quenches the reactive oxygen species.

[A]

I'm going to put in a quick plug for Vitama here because Vitama to pinner off actually has data that it is a direct. The molecule itself is a strong antioxidant in addition to upregulating endogenous antioxidant pathways. And every time they've brought that up, I've been like, you guys are out of your minds, Ross. Have nothing to do with atopic dermatitis. This is baloney. Don't even talk about it. Blah, blah, blah. And son of a bitch, it turns out I was wrong.

[D]

They pay you for.

[A]

Which is.

[D]

They pay you for this advice.

[B]

Yeah, we don't have disclosures on drugs on dermatology, but, yes, germs on drugs.

[D]

I mean, worth every penny.

[B]

Exactly.

[A]

Wait, wait. I got one other thing. I got to ask what you guys think about this. So the other thing that. The stretching made me think about this and Ferris, I don't know if you remember, this was a discussion we had in residency. It's always fascinated me that psoriasis and atopic dermatitis happen in areas that have the most skin stretching. Right? The places where your skin is most actively deformed. Cursor of your elbows, backs of your knees, extensors of those areas. We had a conversation where I was like, do you think it could be, like, the mechanical stretching of your skin that is doing this? And your answer was basically, who the hell knows? Like, I don't know how, but maybe.

[B]

This is in residency, but, yeah, I mean, yeah, I think that there's probably, like, why is one extensor surfaces. I think that there's probably something to, like, trauma, right, to elbows and knees. That's different than maybe the stretching, but, yeah, all right, well, maybe we'll. Maybe we'll figure this out today.

[A]

I always thought that it was the. What the hell do you call it? The sweating in your. In your flexures. But maybe it's both the sweating and this.

[C]

Right?

[A]

But let's. So let's go ahead and move on here. Dan, why don't you. So I. I'm a basic science idiot. I have no idea what happened. Patton's less of an idiot about basic science than I am. Ferris is actually smart. So can you explain your article in a way that I would understand?

[C]

I think you undersell yourself, but I will try. So the lab, for a long time, has been interested in how neurons in the skin are able to control or affect inflammation in the skin. And so we've been Focusing on these sensory neurons in the skin because of course there's all different types of neurons. Some of the neurons can sense painful stimuli. This would be like heat. And they express a receptor that. It's called TRPV1. TRPV1. And that's actually the receptor for capsaicin in chili peppers. These are neurons that are activated by trauma, heat, things like that. We and others have found that these neurons are really required to trigger all kinds of inflammatory pathways in the skin. Whether it's like a psoriasis type or a dermatitis type or just about anything in the skin requires those neurons.

[A]

And Dan, the latest stuff has been that immune cells kind of cluster at the tips of the sensory neurons. I think I saw that somewhere.

[C]

Yeah. So the neurons and the sensory neurons in the skin run along the neurovascular bundles and you can see that lots of cells are hanging out right next to them. Dendritic cells are there. And of particular interest is the mast cell. Right. And they're just hanging out right along those neurons. Obviously they're, you know, they're talking to one another.

[A]

Yep. Now, Dan, I'm going to say right now, when I think mast cell, I think histamine and that's it. Right. Mast cell releases histamine. That's it. I know obviously at this point I've learned better that I'm wrong about that. But I think a lot of people still. You think mast cell, you think histamine? That's it.

[C]

Yeah. Well, mast cells released a lot of histamine. But you know, if you look what's inside the granules, there's like, you know, a witch's brew of different proteases and inflammatory amines. And they also make cytokines and chemokines and you know, all kinds of things. It's this incredibly complex mixture. Histamine is part of it. And you know, if you also think this is apropos of what we're going to talk about, if you also think about how mast cells are activated, right. Everyone is going to think about ige that's made by a B cell and it's pre bound to the antibody, the IgE receptor on the surface of mast cells. And it just hangs out in that state until an allergen comes cross links the ige and then you get mast cells degranulated. That's the classic way of activating a mast cell. It turns out there are many, many, many ways to activate a mast cell. And I think one of the most exciting ones is, is through this New type of receptor. It's called MrGPRX2. And mice have one called MrGPRB2. This is a receptor for many, many types of ligands. For instance, some products of the microbiome on the skin can activate it. Catalysidin, which is made in rosacea by keratinocytes, can activate it. But most importantly for this discussion is that there's this neuropeptide released by the neurons that sense pain called substance P. And substance P is a ligand for this receptor on mast cells and causes the mast cells to be activated. So the neurons, like these pain sensing neurons, when they get activated, they release substance P. And one of the things they do is they cause mast cells to get activated.

[A]

Then is MGPRX2. I don't even know if I got that right. Is it specific to mast cells?

[C]

Because like in mice, it is specific to mast cells. In human, it seems like it's specific to mast cells. But I will defer. There are a lot of people working on MRGPRX2 as a therapy for both urticaria and atopic dermatitis. And it's unclear if it's maybe also expressed on some types of neurons, but certainly mast cells. And it seems within the immune system and within the skin, it's pretty much on mast cells and maybe neurons in certain contexts.

[A]

So that'll be interesting because there is. I'm doing a clinical trial right now with a drug that targets C kit and that is not specific for mast cells. It also is on melanocytes.

[C]

Right.

[A]

So you get hair whitening whenever you attack C kit. So the MGPRX2 is going to be an interesting other target.

[C]

Yeah, so that is under development anyhow. So that's a little bit of background. So we had been working on these pain sensing neurons and we started to think like, well, what about itch? There are other neurons that are responsible for itch. And so we got another mouse strain from Zhang Dong, who's at Hopkins, who's really one of the leaders in this field, and that allowed us to delete one subset of neurons that was responsible for itch. I had this idea that since the pain sensing neurons were required for a type 17 response, that I thought maybe the itch neurons, they would be required for a type 2 response. We played around with that and that unfortunately, like so many of my great ideas, turned out not to be true. But what we did find is that if we were doing models of allergic contact dermatitis, where you put small molecules, you make the mice allergic to the molecule and you challenge them a little bit later that the mice that didn't have this itch sensing neuron, they wouldn't get inflammation right in this allergic contact dermatitis model. And what was interesting, and this was the weird part, this is what got us started, is if you did hapton's that we knew required IGE and mast cells, you needed the itch neurons. But if you did a habden that didn't seem to require ige, it was fine, the mice were fine. And so we scratched our heads for a little while thinking like, well, what are the neurons releasing? And then we just did this super simple experiment where we did the dermatitis model, but we put the mice in Elizabethan collars. Imagine a very small cone of shame that you have for your dog or cat, they make them for mice. And you just put the mice in this cone of shame so they can eat the drink, they're fine, they just can't scratch their ears. And it turns out that you didn't need the neurons per se, you needed the scratching. So you needed the neurons to trigger the itch sensation resulting in the scratch. And that's what you needed for the inflammation.

[A]

That one of our sayings here on derms, on drugs is that one of the most important phrases in all of science is, that's weird.

[C]

Yeah.

[A]

And right when you got away from the itch, when you got rid of the itch neurons and the inflammation didn't happen, and you said, that's weird. Then you did the new experiment. Oh, my God. It's not the itch neuron, it's the scratching. But it's tracking down the weird stuff that you don't expect that leads to big breakthroughs.

[C]

So the hard part was to figure out how does, why is scratching required for inflammation? We talked earlier about all the things that scratching can release in the skin. I mentioned TSLP, we talked about IL33, we went down this list. It's like, yeah, scratching does trigger them. Sorry, when you do the dermatitis, it does trigger them. But plus or minus the Elizabethan collars, there was no difference. That didn't seem to be, at least in this model, triggered by scratching. It turns out that what's happening is you need the scratching to activate the pain sensing neurons. These pain sensing neurons release the substance P, remember? And that binds to the MrGPR x2 on the mast cells and that activates them. But that's not enough. Right. What really needs to happen is if you activate a mast cell using this classic IGE pathway Like a regular allergen will do, you get like level one of mast cell activation. If you activate just with the MrGPRX2, you also get level one of activation. But if you activate both pathways at the same time, you get this big synergistic response and that's what's required for the inflammation. And so that's why scratching was important. And so the idea then is that. So scratching is actually making the mast cells more likely to degranulate. And a way to think of this is that if you have an allergen that's maybe sort of subclinical, like it's not quite enough to trigger the mast cells, if you now start scratching the area, now it'll degranulate and you can get the inflammation going or the protection against the helminth or the protection against whatever it is. Right. So it's like it's lowering the threshold or increasing the efficiency of mast cell activation.

[B]

So is max cell activation through IGE versus through mgrx, whatever. Is it the same kind of activation? It doesn't like, does it cause different substances to be released if you trigger through one or the other?

[C]

Super cool question. So we've known about this for a while. In fact, Brian Kim has a very nice paper on this a number of years ago and others as well before him have found that if you activate a mast cell through IGE or through this mrgprx, two different sized granules are released. Right. So that was known. And it was known that like the cytokine tnf, which is very important for inflammation, if you activate through the FC Epsilon through IgE, you'll get TNF. But MrGPRB2, you don't get a lot of TNF, right. And so, you know, we did this and we found that TNF was one of the main things that was different. But we have not looked properly. I'm sure if anyone like systematically really looks at it in detail, there'll be a lot of changes. And up until now it was kind of unclear why mast cells should be releasing different stuff and what it all means.

[A]

So Dan, Tim and I have been. Or Dr. Patton and I. Excuse me, Even though, by the way, if anybody is watching and thinking why is Patton just not look as good this his computer in addition to using an Android phone, which is just unbelievable. He also, his computer is apparently from 1987 and it crashed.

[D]

I have an Android sponsorship, so I don't.

[A]

So we, we have been talking about if mast cells are actually involved in atopic dermatitis. Because. And, and as I've thought. And my answer, and his answer up till now has been no, like man, because you can put all the.

[C]

Why? Why do you say that?

[D]

I always thought it because mast cell therapies didn't work. Right. That's what we're talking, right?

[C]

What, what mast cell therapy?

[D]

Antihistamines.

[C]

Yeah, well, antihistamines is blocking like one of like 500.

[D]

I know, we're dumb. We're dumb. And then I, I said omalizumab doesn't work either. But omalizumab is ige specific, basically. So you're. Is your argument that there are mast cell pathways that we will discover that are going to completely change our treatment of atopic derm?

[C]

I'm saying I don't know. But I do know that there's quite a bit of pharma interest in blocking the MRGPR x2 pathway. A number of companies, some of which have been acquired by bigger companies and there are a number of clinical trials going on and I'm not privy to them, so I don't know if they're working. I would think it'd probably be very effective in urticaria. Right. In urticarial related disorders. And whether it also works for atopic dermatitis. I think it probably should, but I don't know the answer to that. But I bet we're going to find out pretty soon.

[A]

So Dan, if I can. Let me see if I can summarize how I think about this now and tell me how wrong. I'm sure I'm wrong, but the question is how wrong? So, because I'm always thinking from an evolutionary perspective, why would it have gone this way? And so I now think of it as being the scratching activates an immune response that is not just removing stuff from your skin, but is also, let's say that the bug that bit you put a little bacteria in there too and you start scratching it before it turns into an infection. You're like priming your anti infection response is that.

[C]

I think that's, that's 100% right. So we focused up till now talking about how scratching makes more inflammation, which, you know, I think the upshot from this first part I've talked about is that scratching makes your rash worse, makes the inflammation worse. And I think this tracks very well with everyone's experience, right? If you have eczema, you scratch it, it feels awesome, but you're going to pay for it. Your rash is worse. If you have a mosquito bite and you ignore it, it usually Goes away pretty quickly. But if you scratch it, you know, you'll get, you know, a persistent urticarial papule that can last for a week or so. So, you know, the question we asked at this, this is the second half of the paper is, you know, you get more inflammation from scratching. Is there a benefit from it? What we found is that if you look at the microbiome of the skin of these mice, when the mice scratch, their microbiome is less diverse. Some of the bacteria are no longer present. And if you do a model, a staph aureus model, this is just really an epidermal staph or like an impetigo model, basically, that the scratching reduces the amount of staph on the skin by a fair bit. If you either have mice where they don't sense the itch, where you get rid of the itch sensing neuron, or if you put those cones of shame on them so they itch but they can't scratch. Now they have a normal level, they have a high level of staph. So the idea then is that scratching, while being detrimental, if you have an allergic situation, like eczema, is actually beneficial, at least in the short term, because it helps reduce the amount of staph aureus on our skin. And I think that's one of the reasons why scratching may have evolved, may have persisted. And I think it's also one of the reasons why it feels so good to scratch an itch because it's actually a reinforced behavior. Right. It's a good thing.

[B]

Fascinating. So do you think this has a role in like bullous pemphigoid, like thinking about things that really itch and like, do you think that the itchiness of bolus pemphigoid causes sort of out of control inflammation and older people, and that's why we get recruitment of eosinophils and blistering. Or I, I don't know. Maybe it doesn't.

[C]

It's super interesting question. I don't know. Do you? I don't know.

[D]

So if you. But now we think of these medications that let's get rid of itching. You know, it's like what gets rid of itching the quickest? Is itching purely evolutionary? Do you think we still derive a benefit or do you think there's any sort of potential harm of, you know, if you could completely knock out itching, do you think that would hurt us?

[C]

Only if you had scabies.

[D]

Okay.

[C]

Right. No itching. Itching. Okay. Itching is like a useful Behavior. Right. Useful sensation leading to a often useful behavior. Right. So what's the point of pain? Right. Pain is to let you know that a. You've got some trauma or something going on. You should attend to this problem, fix it. But also you should remember, it lays down memories that whatever you just did that caused that pain, don't be an idiot and don't do it again. Right. But scratching is very different. It's reinforced. Right. So you want to do it more and more and more. So I think they're fundamentally different.

[A]

Interesting.

[B]

It's the carrot with it.

[A]

Dan, this has been a fascinating discussion that has been a ton of fun, and we're now going to move on to what it turns out is everyone's favorite portion of the show, where Dr. Patton is going to pull out his trivia machine, which is really just himself.

[C]

It's not on his laptop, is it? That would be trouble. It's not a what? It's not on your laptop, is it?

[D]

I printed it out. I have a backup plan.

[C]

Wow. You use paper. Impressive.

[D]

Paper and printer.

[A]

All right, so, Dave, we reviewed the rules before we started. Dr. Patton, let's go.

[D]

Yeah. By the way, as I was reading your paper, I kept thinking, you really need to make, like, if you give a mouse a cookie, but with your research, like, if you give a mouse diphtheria toxin, you'll knock out MrG Pra2 neurons. If you knock MrGPRT with, like, little cartoon drawings. And, like, I would have understood this much, much better.

[C]

There is. Did you get to Supplemental Figure 48? Because there is over there.

[D]

No, no. Like, that's the thing that kills me. There's. You had, you know, however many experiments, six separate experiments. And then you're reading along and it's like, oh, check supplementals. And, like. No, no, I. I don't understand these six experiments.

[C]

Well, yeah, yeah. It's just a necessary evil. No, no, no.

[D]

It's. It's. It's just. It's smarter than. Way smarter than I am. So it frustrates me.

[C]

All right.

[A]

And it's just differently smart than you. Differently smart.

[D]

My therapist, Matt. All right, so these are questions about trivia, about pruritus, which I. That's how I say it. Stop me. All right, here we go. What cartoon duo known for their over the top violent antics often entertains Bart and Lisa on the Simpsons? That's Kaplan by a hair. By a hair what?

[B]

1955 is not ironic that Kaplan beat me by a hair. That's all I'm gonna say. Go Ahead.

[D]

Oh, ouch. That's not nice. What 1955 film features Marilyn Monroe in her famous white dress scene standing over a subway grate with her skirt billowing upward?

[C]

Seven years.

[A]

Seven year itch.

[D]

Kaplan again. He's just.

[A]

What was it?

[D]

It's seven year itch. But Kaplan's in earlier. From where I am just. He's quicker. He's quicker on the bus.

[B]

North Carolina. It's like why they put the traders in New York.

[C]

Well, you could be in picture.

[B]

Electronic delay.

[D]

All right, all right, third and final question. What bacterial disease caused by Bartonella Henseley shares its name with a Ted Nugent song?

[B]

Cat scratch fever.

[C]

Yep.

[D]

Once Zyrus043. Man.

[A]

Ferris beat me to that.

[B]

I did.

[D]

You may be on a delay. You're a little choppy today.

[A]

Okay, that's it.

[D]

All right.

[A]

So again, I remain on the losing streak for the entire season, so we'll stick with that.

[C]

Can I ask Matt, since. Since I had two out of three, can I get your voice on my voicemail like a prize, or do I get to choose any of the panelists?

[D]

Wait, wait, don't tell me type thing? Yeah.

[A]

Do you know what my voicemail actually says? Don't leave me a message. That's it. It's the whole voicemail. All right. Well, Dan, thank you for joining us. This was such a fun discussion, and I want to thank all of our listeners for joining us as well. If you got questions, comments, ideas for topics we should cover on the show, shoot us an email at questions on dermsondrugs.com Again, that's questionsurmsondrugs.com and I hope you learned a few things. I hope you laughed once or twice. Mostly I hope you're planning to join us next week. So until then, I'm Matt Zyrus.

[D]

I'm Tim Patton.

[B]

And I'm Laura Faris. And we are Derms on drugs.