Molecular chain reaction drives skin injury and psoriasis

Most of us think of the immune system as a mysterious army that the body summons in response to a threat.

We’re familiar with some of the inflammatory molecules that come into play when the immune system goes awry, as it does in psoriasis. And some of us benefit greatly from treatments that thwart known drivers of inflammation, such as tumor necrosis factor-alpha and interleukin-17, which are targets of some biologic drugs.

The inflammatory response is rooted deep in our biology—but it can also be found right on the surface of the skin, said Dr. Ling-juan Zhang, first author of an article detailing the discovery of a previously unrecognized molecular pathway in skin cells.

The findings were published in the journal Immunity on July 19, 2016, based on a study performed at the Gallo Lab at the University of California, San Diego with grant support from the National Institutes of Health and the National Psoriasis Foundation.

A $50,000 NPF grant helped fund the study. The grant was awarded in 2009 to Dr. Richard Gallo, a dermatologist and researcher at the University of California, San Diego.

To date, NPF has awarded more than $15 million in grants to researchers studying psoriatic disease. To read about our most recent awards, click here. Interested in supporting research at NPF? Click here.

“Instead of studying the entire immune system, our lab focuses on the skin itself as the trigger of inflammation,” Zhang said. “We’ve been teasing out the complex interactions between tiny molecular components found in keratinocytes, the most abundant cells on the surface of the skin.”

As our outermost layer, skin is our body’s first line of defense against potentially harmful invaders such as viruses and bacteria. As such, skin is a critically important part of the human immune system.

Usually it works extremely well, rushing blood, antibodies and a variety of immune factors to the scene of an injury.

But sometimes, for reasons that remain poorly understood, the skin’s protective processes turn dysfunctional. Immunity goes into overdrive. Normal skin cells go rogue.

In psoriasis, the normal process of skin cell turnover speeds up, so dead skin cells pile up to form plaques.

“Molecular common ground”

The Gallo research team decided to investigate the similarities between normal responses to skin injury and psoriasis. They did so in light of a common occurrence among psoriasis patients known as the Koebner phenomenon.

“In the Koebner response, psoriatic plaques can form on healthy skin near the site of an injury,” said Zhang. “The Koebner phenomenon led us to an exploration of the molecular common ground between early wound healing and psoriasis. As expected, we observed the same pathway at work in both settings.”

Their abbreviations can make the molecules involved in that pathway—like LL37 and TBK1—sound a bit like obscure weapons systems out of science fiction. But at a cellular level, they’re very real.

According to Zhang, one protein—MAVS for short—could emerge as a target in the development of new treatments. MAVS operates at the epicenter of a whole cascade of events that drive psoriasis.

Interrupting the ability of MAVS to do its job could be a promising way to go, Zhang explained.

“Targeting T cells [immune cells] has been shown to be an effective treatment for psoriasis,” she said, “but the disease often reoccurs when patients stop treatment. We foresee a time when treatments that ease an overactive immune system could be combined with newer drugs that target MAVS in skin cells.”

That pairing would be a double whammy against both types of disease signals—those that are triggered in the skin and those that come from immune cells located “upstream,” meaning further away from the site of symptoms.

Zhang also foresees a new trend in basic psoriasis research. Instead of focusing on one cell type, researchers will increasingly explore the cross-talk between various types of cells along with the micro-environment in which the disease develops and takes hold.

To read more about NPF’s investment in research examining connections between the skin and immune system, click here.

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