Understanding psoriasis is like trying to assemble a puzzle without enough pieces. You do your best to put it all together, but something still seems missing.
The pathogenesis of psoriasis—the scientific term for the way the disease develops in the body—involves a number of things that, on the surface, seem unrelated.
Psoriasis resembles a rash, but it’s set off by your own immune cells. It can start after you get a scrape or scratch through a process called Koebnerization. But it can also be triggered by a strep infection deep inside your throat. And even though you see it on your skin, your doctor might recommend treating it with pills or injections.
A team of researchers funded by the National Psoriasis Foundation may have found a missing puzzle piece that could fit all of the different parts of psoriasis together. It’s a protein called Rac1, and according to research from the same team, removing it from the picture by blocking it in the body might effectively treat the disease.
According to an article the team published in July 2016 in the Journal of Clinical Investigation, Rac1 drives the interaction between the skin and the immune system that leads to psoriasis.
Understanding the way it functions in people without psoriasis helps explain how it could be the culprit behind such a multi-faceted disease.
From the skin to strep
Rac1 has three main functions that made it a likely candidate to be involved in psoriasis, explained Dr. Marten Winge of Stanford University, the lead author of the Journal of Clinical Investigation paper.
Winge won a 2015 National Psoriasis Foundation Amgen Medical Dermatology Fellowship that helped fund this research.
Previous studies have shown that Rac1 helps heal skin injuries, becoming activated in skin cells “when they migrate in to close the wound,” said Winge. “Also, Rac is important for normal skin differentiation and growth.”
Since psoriasis can start after a skin injury and is characterized by abnormal skin cell growth, those two things alone make Rac1 a likely suspect in psoriasis pathogenesis. When you add in the part it plays in streptococcal infection, things get even more suspicious.
Strep bacteria can also trigger Rac1 activation, Winge said. The bacteria can stimulate skin cells called keratinocytes so Rac1 springs into action the way it does for a skin wound. That helps the bacteria travel throughout the cells.
“It kind of abuses that system to activate Rac and penetrate the skin,” Winge said.
That’s how Rac1 works in healthy people—or people who get healthy as soon as they recover from their bout with strep.
But when Winge and his colleagues—including Dr. Peter Marinkovich, winner of a 2011 Translational Grant from NPF—studied how Rac1 works in psoriasis, they noticed some important differences.
Marinkovich is a dermatologist and researcher at Stanford and the senior author of the journal paper, which was funded in part by the NPF grant.
Stuck in the middle between the skin and the immune system
The research team found that Rac1 was increased in people with psoriasis. On top of that, the researchers found that Rac1 stayed active in people with psoriasis long after it should have quieted down.
One explanation could be that people with psoriasis have a genetic predisposition to increased levels of Rac1 activation, Winge said. That might explain how some of the genetic risk factors linked to psoriasis function in the skin.
Another explanation has to do with the immune system and how it interacts with the skin.
“The other reason you could think why Rac1 would be persistently high would be that you have the keratinocytes stimulated in an abnormal way by immune cells,” Winge said.
In normal skin, the immune system response shuts off as soon as the injury is gone. But in people with psoriasis, the immune system stays stimulated whether or not an injury is present.
Through a series of experiments involving mice engineered to have a psoriasis-like disease and skin cells from people with psoriasis, the researchers learned that when it comes to understanding how Rac1 drives psoriasis, the immune system and the skin are equally to blame.
“What is the ultimate culprit?” Winge asked. “I think that it’s both.”
“Even though Rac1 activation is necessary for development of psoriasis in the keratinocytes, it needs immune-derived stimulus,” Winge explained.
New topical treatment?
Because the skin and the immune system are equal players in psoriasis pathogenesis, stopping Rac1 in the skin could be just as effective as stopping it in the immune system, Winge explained.
“In principle, that would mean that it would open up the possibility for a topical delivery of any Rac-inhibiting agents,” Winge said. “You don’t have to perturb the immune system at all really. You just have to break the keratinocyte part of the cycle.”
Many effective drugs, such as biologics, are available today that can clear even the toughest cases of psoriasis. But these are systemic treatments that suppress some component of the immune system.
Marinkovich and Winge are currently testing a potential therapy that could block Rac1 in the skin, leaving the immune system alone.
One more reason to support NPF research
Marinkovich also won a 2016 Translational Research Grant from NPF to continue his work in this area.
Winge’s fellowship ensured he could dedicate as much attention as needed to the project.
“Getting this fellowship has been absolutely critical to being able to devote the time to go into the detail that’s required to understand the basic mechanisms of this very complex disease. If I didn’t have the support of NPF, I wouldn’t be able to do this full time,” he said.
For Marinkovich, NPF funding also played a crucial role in driving his research forward, particularly in the early stages of studying Rac1 in mice.
“Once we had the funding from NPF, we were able to do a lot more detailed characterization of the mouse. Then we embarked upon a study to correlate the importance of Rac1 in human psoriasis keratinocytes and skin,” Marinkovich recalled.
“I’m grateful for the support NPF has given me,” he said.
Applications are now being accepted for Psoriatic Disease Research Fellowships. Click here to learn more.