Psoriasis researcher examines nervous system’s role in perpetuating disease

Many dermatologists have seen the phenomenon, but can’t explain it. It starts when a psoriasis patient undergoes knee joint replacement surgery or has an accident resulting in skin denervation. Amazingly, the skin disease disappears on the treated or injured knee.

READ: Researchers isolate psoriasis triggering proteins 

Prior to a study by Nicole Ward, Ph.D., in 2011 in the Journal of Investigative Dermatology, scientists had only hypothesized this phenomenon was due to skin nerve damage. A newly funded National Institutes of Health (NIH) study, which was started in July 2013 by Dr. Ward and colleagues, not only follows up on her previous work, but could also open the door to new therapies for chronic psoriasis sufferers.

Dr. Ward, associate professor of dermatology at Case Western Reserve University School of Medicine, Cleveland, has received three NIH grants to study the mechanisms of psoriasis. The most recent is to investigate the nervous system’s role in in the disease.

Dr. Ward says her work in psoriasis started almost by accident.

“When I started my own research lab, I was interested in studying how blood vessels and nerves in the skin interacted, and why they seemed to pattern each other. In developing experimental methods to study how those two systems interacted, I serendipitously created my first mouse model of psoriasis, which was the KC-Tie2 mouse. That’s the mouse model that I originally published and still study to this day,” Dr. Ward says. “That started my interest in studying inflammation, and how it’s sustained and initiated specifically with respect to psoriasis.”

NEXT: Identifying protein culprits

Identifying protein culprits

In 2011, Dr. Ward and colleagues used the KC-Tie2 mouse model and developed a surgical method to mimic what doctors had been talking about anecdotally (Ostrowski SM, Belkadi A, Loyd CM, et al. J Invest Dermatol. 2011 Jul;131(7):1530-1538).

READ: Case Western gets $1.9M grant for psoriasis research

“We surgically went in and eliminated the nerves from the skin and, lo and behold, the disease in the mouse model went away,” Dr. Ward says. “We were able to figure out what’s going on in the cell bodies of those nerves in the skin, which are actually found along the spine in a structure called the dorsal root ganglion (DRG).”

The researchers dissected the cell bodies of the nerves to study gene expression changes and identified two molecules that were increased: calcitonin gene related peptide (CGRP) and substance P.

“We were able to put (the proteins) back into the mouse skin under denervated conditions (when the nerves were surgically removed), and showed the disease came back. And we were able to inhibit those proteins in the mouse when the nerves were present and showed that the disease got better,” she says.

These proteins, according to Dr. Ward, appear to drive and maintain skin inflammation. The most recent NIH grant allows Dr. Ward and colleagues to determine these molecules’ direct and indirect effects on cells.

“We know there are certain cells that change in a predictable temporal manner following denervation. What we’re going to do is try and figure out how these molecules - how these proteins - are actually driving the disease,” Dr. Ward says.

NEXT: Research team's goal

The research team’s goal is to better understand, at the basic science level, how CGRP and substance P are critical for psoriasis pathogenesis. The long-term goal is to potentially develop drugs or therapeutic targets that can directly inhibit these proteins or modify the actions these proteins have with individual cells, according to Dr. Ward.

The new two-year study Dr. Ward and colleagues started only months ago is considered translational research. Part of the work involves growing cells from mice and looking at how these proteins directly cause changes in the cells. The researchers will then retrieve skin cells and immune cells from psoriasis patients and controls and conduct similar experiments using cells isolated from those subjects.

Dr. Ward’s hope is that the findings obtained from her basic science work will be useful for practical applications that enhance human health and well-being.

Disclosures: Dr. Ward is a consultant to Novartis, Amgen, Eli Lilly and Galapagos.