Psoriasis, Diabetes and Other Inflammatory Conditions

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Today on The Fundamentals, we have a conversation with Dr. Sonya Wolf-Fortune, Assistant Professor of Pharmacology, whose work focuses on investigating the underlying mechanisms of psoriasis, diabetes, and other inflammatory conditions. Dr. Wolf-Fortune is trying to uncover what sets off the cascades of inflammation related to these conditions and related diseases.

Dr. Wolf-Fortune Profile

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Transcript

Kelly Malcom:

Welcome to The Fundamentals, a podcast where we explore biomedical research here at Michigan Medicine. Research is fundamental to University of Michigan's mission to improve the world. On each episode, we'll meet the people behind the research, learn more about their fields and the fundamental questions they are trying to answer.

I'm Kelly Malcolm, a science writer and communication strategist for the University of Michigan Medical School. This season, we'll start by explaining a little bit of the history behind the questions our experts are asking and get a glimpse into the future of healthcare.

Few diseases carry as much stigma as those affecting the skin. A recent survey found that 85% of people with psoriasis in the US experience discrimination and humiliation because of their skin. This discrimination has persisted for centuries. According to the Psoriasis and Psoriatic Arthritis Alliance, during the Middle Ages, people with psoriasis were outcasts who were required to carry a bell or a clapper to announce their approach and who could only mix with other quote-unquote lepers.

Medical historians believe that many people with psoriasis, which is an inflammatory disease, were lumped in with people with leprosy, an infectious disease caused by the bacteria mycobacterium leprae. They were thus banished to live in leper colonies to avoid spreading their condition to others. However, psoriasis, which appears on the body as thick red skin with silvery white scales that itch or burn, typically on the elbows, knees, scalp, trunk, palms, and soles of the feet, is not contagious. It was first described by Robert Willan, considered the father of modern dermatology, in the early 19th century and affects two to 4% of the world's population.

People with psoriasis, which has no cure, often have other medical conditions, including psoriatic arthritis, cardiovascular disease, and metabolic conditions like diabetes. In fact, people who have plaques that cover more than 10% of their bodies have an almost 65% higher chance of developing diabetes. Researchers like our guest, Dr. Sonya Wolf-Fortune, Assistant Professor of Pharmacology, are investigating the underlying mechanisms of psoriasis, diabetes, and other inflammatory conditions, trying to uncover what sets off a cascade of inflammation and disease.

Welcome, Dr. Wolf-Fortune.

Dr. Sonya Wolf-Fortune:

I'm so glad to be here.

Kelly Malcom:

We're just going to jump right in. How are psoriasis and diabetes linked?

Dr. Sonya Wolf-Fortune:

It's really interesting. Whenever I talk with people and I mention the research that I do, and I mention that I examine the link between psoriasis and diabetes, typically the first comment I get is, "I didn't know that they were linked," or associated, and that the literature actually supports this link between psoriasis and diabetes, and it's also seen within the clinical setting. And psoriasis and diabetes have this really interesting relationship where people with psoriasis have increased risk for type 2 diabetes, and vice versa, people with type 2 diabetes have increased risk for psoriasis.

But even though this has been shown, the molecular mechanisms that link these two diseases, that really is not clear. What we do know is that people with psoriasis seem to have increased development of insulin resistance, and we know that's a key factor in development of type 2 diabetes. And then it seems that increased severity of psoriasis is also associated with increased risk for type 2 diabetes, as well as both psoriasis and type 2 diabetes seem to share common inflammatory pathways. And so my lab is really interested in trying to understand the key inflammation pathways that are driving metabolic dysfunction and increased risk for type 2 diabetes in order to hopefully be able to target these pathways in the future to try and prevent this development.

Kelly Malcom:

What's the connection between the amount of skin that's affected and diabetes, or do we know yet?

Dr. Sonya Wolf-Fortune:

Yeah. I think the way that it's presented is that they have increased area of psoriasis covering their body, and so with that increased area, that seems to be associated with increased risk. But in terms of severity, we do know increased severity of the lesions seem to be associated with increased risk of type 2 diabetes, but I think there's still a lot of work to be done in that area.

Kelly Malcom:

Okay. What are the existing therapies for psoriasis? Is there a cure?

Dr. Sonya Wolf-Fortune:

You'd imagine, for a disease that's been around for quite some time, that there would be, but what we've been able to learn over the years is that psoriasis is a complex disease, and what was once thought to just be contained in the skin, we now know patients with psoriasis, some patients, exhibit inflammation throughout the body. And there are also multiple triggers for psoriasis. You have infections, medications, stress, diet, and this all results in a overactive immune system.

And so, while current treatments can decrease that inflammation and some of the symptoms of psoriasis, it's difficult to actually eliminate the underlying immune system dysfunction. And so some of those difficulties come from not fully understanding what's driving that initial dysfunction in the immune system as well as the heterogeneity that occurs within psoriasis itself. And so you can imagine someone that has inflammation throughout their body and has this dysfunction in their immune system that some of these factors might be contributing to that increased driving of metabolic dysfunction and risk for type 2 diabetes.

Kelly Malcom:

Okay. Is there a genetic link for psoriasis and diabetes?

Dr. Sonya Wolf-Fortune:

Yeah. There is. There are some more recent studies, genome-wide association studies, that have actually suggested a link between psoriasis and type 2 diabetes. And so some of the genes that have actually shown up in these studies may actually regulate some of those inflammation pathways associated with both psoriasis and type 2 diabetes. But there's still a lot of functional studies that need to be done to understand the role of these genes in regulating these inflammation pathways and how they're contributing to psoriasis progression. But that area of examining genetic and epigenetic linkages between psoriasis and type 2 diabetes is continuing to grow, because if we can understand the genes that are causing this linkage and how they're manipulating pathways, then we can understand maybe how to target those genes specifically or the pathways that they're manipulating.

Kelly Malcom:

Okay. I know, when I'm watching TV, I see a lot of ads for drugs for psoriasis, and I can't think of a name off the top of my head, but what are those drugs doing? Because it also seems like they're used to treat other conditions.

Dr. Sonya Wolf-Fortune:

Yeah. You're referring to biologics?

Kelly Malcom:

Yeah.

Dr. Sonya Wolf-Fortune:

Yeah. Biologics are interesting. They are medications that will target a specific inflammation pathway within a disease. And when in the context of psoriasis, these biologics contain antibodies. And so antibodies are these Y-shaped proteins that can specifically target a specific protein in the body and inhibit its function.

And so in psoriasis, one of the ones that you might've heard of is Humira, all those commercials every time you're trying to watch something. And Humira, it contains antibodies that can target and inhibit the TNF-alpha inflammation pathway to help decrease psoriasis inflammation. And so, as you mentioned, you hear then this whole list of diseases that come along with this commercial. And so that's because, as I mentioned earlier, diseases can share common inflammation pathways. And so you can imagine that this particular biologic, Humira, can be used in psoriasis to target the TNF-alpha signaling pathway, but it could also be used in other diseases that may also have this inflammation pathway as well.

Kelly Malcom:

Okay. That TNF-alpha pathway is usually triggered by what or for what reason?

Dr. Sonya Wolf-Fortune:

The TNF-alpha pathway, it's driving inflammation within psoriasis. The exact trigger of its activation, that's still something that is still being teased out, but it ultimately is driving inflammation within psoriasis disease.

Kelly Malcom:

But under normal circumstances, you need it to what, fight infections or ...

Dr. Sonya Wolf-Fortune:

Yeah. Under normal situations, TNF-alpha could help to alleviate injury to the skin. You might see it showing up there.

Kelly Malcom:

It seems like the GLP-1 drugs are this almost miracle drug for diabetes. Is there any underlying mechanism where they could also affect other forms of inflammation or is it just a totally different system or mechanism?

Dr. Sonya Wolf-Fortune:

Yeah. That is another great question. I did attend a seminar recently, and they were talking about where they were doing some mouse experiments where they were examining the GLP-1 and didn't just see improvements in inflammation in the context of obesity or metabolic dysfunction regulation, but also in other aspects of inflammation throughout the body. And so I think it could have some promise in those areas as well.

Kelly Malcom:

Okay. How did you become interested studying inflammation?

Dr. Sonya Wolf-Fortune:

I became interested in studying inflammation research just because, when you think about inflammation, it plays such a large role in everyday life. You can have over-inflammation and that can cause body damage, but then you also need inflammation, as we mentioned, to help regulate infections and help with healing when you get an injury. And so it's really important not only for driving body injury, but helping us with our everyday life, helping us to function normally.

And so I think I just became very fascinated with all of the avenues inflammation is important for, and I became specifically interested in studying skin inflammation when I went into graduate school, and I studied systemic lupus erythematosus, which is an autoimmune disease, and this was actually where I got my first glimpse into how powerful skin inflammation can be in driving systemic inflammation throughout the body.

And then, as a postdoc, I became interested in the area of diabetes and the complications associated with diabetes, and one of those is chronic skin inflammation conditions. And so I studied diabetic wounds initially and then became interested in other skin conditions associated with diabetes, like psoriasis, and so was very fascinated by that connection between psoriasis and type 2 diabetes, and also in the fact that there's such this gap in knowledge in understanding the link between the two diseases.

Kelly Malcom:

What drew you to come to U of M? Was it a particular lab or PI?

Dr. Sonya Wolf-Fortune:

Yeah. I think what drew me to University of Michigan, I guess, grad school or as a faculty member, I think, is the environment here. It's very collaborative and I can always have access to instruments, and even I'm interested in having my work be as translational as possible, and so I've been able to find a lot of clinician-scientists who have been able to collaborate with me so that I can have access to patient samples and make sure that I'm asking the right questions with my research. I think it's definitely the environment and the PIs here, and it's just a really wonderful place to be.

Kelly Malcom:

Anyone in particular you want to give a shout-out to?

Dr. Sonya Wolf-Fortune:

I have quite a few collaborators. I have been able to work with, on the skin side, Johann Gudjonsson, Michelle Kahlenberg, and Alex Tsoi. And then, on the diabetes side, I have been able to work with Carey Lumeng and Katherine Gallagher. And so all of them have really come together and it's been so helpful in helping me get started. But as a budding assistant professor, I'm always open and looking for new collaborations too.

Kelly Malcom:

What do you think is in the future for inflammation research? I know it's one of the topics that it's so hard for us to nail it down because it's so broad. What do you think are maybe the most promising directions to figuring out what's happening in the context of inflammation?

Dr. Sonya Wolf-Fortune:

Yeah. It is broad and it's complex, and there's so many factors that contribute to it, and then it can be different from disease to disease, and then you have the heterogeneity of the disease that contributes to that complexity. And so I think one of the things that, moving forward, is people will continue to really try and tease out those complexities that are driving inflammation and contributing to this process within their disease of study. And then also there's this push for personalized medicine because you have that heterogeneity and inflammation between patient to patient within diseases. And then I think what we're starting to see, too, is the sharing of that knowledge between diseases, because some of these diseases do share common inflammation pathways, and so being able to share that informationflammation with one another can really help each of the fields move forward.

Kelly Malcom:

Do you have any tips for young researchers who maybe they want to come up with a cure, maybe that'll be you, but maybe someone else will want to come up with the ultimate cure for these inflammatory conditions, or just researchers in general? Do you have any tips?

Dr. Sonya Wolf-Fortune:

Yeah, such a great question. I think, as a new researcher coming into the field of inflammation, I feel like one of the things that's nice is everyone receives their own unique training. And so I feel like you have, like in my instance, of receiving training inand skin inflammation and the area of diabetes. You need someone who has received training in the skin or received training in diabetes or some of these other areas to come into the field and bring their unique perspectives, because I feel like, once someone comes in with their unique training and their unique view, that's how you really get some of these really interesting questions that really probe and explore and will hopefully help to continue to open up this area of inflammation and research.

Kelly Malcom:

What does the future hold for your lab and research?

Dr. Sonya Wolf-Fortune:

My lab is really interested in trying to understand, as I mentioned, the key inflammation pathways that are associated with driving metabolic dysfunction within psoriasis patients, and particularly focused on epigenetic changes that are occurring in the context of psoriasis within structural cells like keratinocytes and immune cells, and trying to understand how it's regulating phenotype within the context of psoriasis, as well as understanding structural immune cell crosstalk, so how keratinocytes communicate with immune cells to manipulate and change their phenotype, both locally and distant, in the context of psoriasis and may drive some of these metabolic function changes.

Kelly Malcom:

Okay. And what are some examples of epigenetic changes for those who might not know what that means?

Dr. Sonya Wolf-Fortune:

Your DNA is tightly wound around histones, and so these histones can have modifications to their tails that can cause opening or closing of the DNA making genes more or less accessible. And so I am interested in the enzymes that cause changes to the tails of these histones, and in turn, dictate opening and closing and affect gene transcription. And so these enzymes can then influence the phenotype of these cells to either make them more inflammatory, less inflammatory.

Kelly Malcom:

Okay. And so is that the mechanism by which maybe something in the environment could be triggering the disease?

Dr. Sonya Wolf-Fortune:

Yes.

Yeah, so definitely environmental factors can have an effect on epigenetic changes.

Kelly Malcom:

Okay. Again, thank you so much for being here. I've learned a lot. I hope that there are new therapies on the horizon for these conditions that affect so many people, and I appreciate all the work you're doing.

Dr. Sonya Wolf-Fortune:

Well, thank you so much for having me.

Kelly Malcom:

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