Transcript
Dr. Neal Bhatia (00:05):
Hi, I'm Dr. Neal Bhatia. I'm Chief Medical Editor of Practical Dermatology, and this is another installment of Dermatology Dialogues, and I'm thrilled to have my friend, Joshua Grosshandler, from the great state of Ohio. Dr. Grosshandler, welcome.
Dr. Joshua Grosshandler (00:19):
Thanks, Neal. I appreciate it.
Dr. Neal Bhatia (00:21):
Please state your name, rank, and serial number, and where you work and all that?
Dr. Joshua Grosshandler (00:25):
We got to do it all right to keep it at kosher. Like you said, Josh Grosshandler, I practice as a private practice dermatologist in one of the suburbs of Columbus, Ohio. Take care of everything, all things dermatology, do the surgeries, do the cosmetics, just enough to keep my wife happy. You got to do those things.
But no, and also work with some different residents. I think I'm technically a clinical associate professor at the Ohio University Heritage College of Medicine. So again, thanks for having me, and excited to talk all about this.
Dr. Neal Bhatia (01:03):
That was very cool. I mean, you and I have been in a lot of group meetings together, but now we get to play a little tennis, which will be fun.
Dr. Joshua Grosshandler (01:09):
Very, very true. Very true.
Dr. Neal Bhatia (01:11):
So, the topic today is the aryl hydrocarbon receptor pathway, as well as just looking at different mechanisms behind, again, not looking at immunosuppression per se, not looking at modulation. We're just looking at pathway-driven elements that cover all sides of the immune pathways, and then just trying to put it into clinical practice.
So with that, we'll just go right at it and think how does the aryl hydrocarbon receptor pathway work? How does the agonist mechanism of action work? And let's just think about all these different components. Obviously, we know about Janus kinase, we've seen where phosphodiesterase 4, those pathways work in inhibition. And again, those are phosphorylation-driven. But think a little bit about what the aryl hydrocarbon pathway and that receptor blockade or agonist pathway looks to you. What would you describe it as?
Dr. Joshua Grosshandler (02:04):
Yeah, I mean, I think it's a great question, and I think it's one, to your point, we're really familiar with a lot of these other pathways. We have so many different drugs and we've had them for a while. I think aryl hydrocarbon receptors have been something... They've been around for a long time, but I think flew under the radar for quite a while, except in some other things that maybe we'll talk about here in just a little bit.
But I think I want to break it down a few ways. I think the one line is really the aryl hydrocarbon receptor is how the skin reads the environment. It's kind of this master regulator of homeostasis. And to really dig into it, basically think of it as this receptor. It's everywhere. It's in our skin, it's in our gut, it's in our lungs, it's in our brain, it's in our eyes.
And what's really interesting about it is it's something that sits in the cytoplasm. So it's not in the outside of the cell, it's sitting in the cytoplasm. And we have all these signals. And so basically, there's this thing called a ligand, and a ligand is... Think of the signal. And what happens is, if you want to break down the definition, aryl hydrocarbon receptor is a ligand-activated transcription factor.
But what that means to me is you have these signals, they're coming from everywhere. And so really, some of these signals are in our environment, they're in our gut, they come from how the sun interacts with our microbiome and the skin and producing things. So these signals, they bind to this receptor in the cytoplasm. That aryl hydrocarbon receptor then goes inside the nucleus.
And when it goes inside the nucleus, it basically pairs up with something called an aryl hydrocarbon-receptor nuclear translocator, or ARNT is what most of us use for short, and it's switching on and off the genes. And when it's doing this, that's how we're getting the various responses that we're seeing, again, whether it be a good response, helping us, or sometimes even can be a negative response, which again, I think we'll go into.
But again, I guess another way to think about it and try to make it simple, I think of these Nest Learning Thermostats. I don't know if you have one at your house, Neal, but I've got one. And it's looking at temperature, it's looking at our humidity, and it's looking in all these different rooms. And we have the central app that's controlling everything, but it's looking at, is your temperature, is it high or is it low? And then it's making an adjustment. It's turning on your air conditioner and it's turning on your furnace to regulate. And so again, I think as a mainstay, really talking about these, it's just really this master regulator, but taking in the environment.
Dr. Neal Bhatia (04:46):
Yeah. No, I'm a little older than you. I always use the stereo example. You have bass and treble and everything else that adjusts, and then eventually you get to the sweet spot. But that's a perfect description of, again, how it's looking at the surveillance of all processes.
And in many ways, the aryl hydrocarbon receptor complex is agnostic to a Th1 pathway or a Th2 pathway from that respect. Similar to what we talked about with phosphodiesterase 4, just basically blocking the phosphorylation and the conversion. And I think your other point about where does AHNT fit into the gene expression blockade, and I think that's another important puzzle piece with that. So that's a real good description.
I think from there too, like you said, it's not just in the skin, it's all over the place. But when we think about delivery of topicals, for example, with steroids, we always think about receptors having to upregulate or compensate with... That's how we get to tachyphylaxis and needing more to accomplish the same goal. Do you think that's a similar process when you block aryl hydrocarbon receptor?
Dr. Joshua Grosshandler (05:53):
It's a good question. And one of the things about aryl hydrocarbon receptors that are interesting is you can have too much activation and that can lead to some problems. It's kind of like the Three Little Bears. There's too little, just enough, and too much, and really, you want to find a sweet spot. One really interesting thing that happens with these receptors, it has its own shutoff switch. It's supposed to be able to break things down. And so it actually takes that molecule that it's sensing, the ligand, and it has the ability to break it down.
And so in some senses, you don't necessarily have the tachyphylaxis if that's working correctly. Now, again, we have some toxicologic problems within dermatology and otherwise that can come from that receptor being stimulated way too long. And again, I think we'll get into that probably here in a little bit. But yeah, I mean, I think if you look at some of the studies that were done with one of the medications that we have, tapinarof, they really did not see tachyphylaxis in that study. So I think that reiterates what a lot of us know, again, when you're using that just enough.
