Houston, Texas, USA : A lipid that helps keep skin cell turnover on track may help restore healthy turnover in psoriasis, investigators say.
Topical application of the lipid phosphatidylglycerol, or PG, on a mouse model of psoriasis reduced inflammation as well as characteristic, raised skin lesions, they report in the Journal of Investigative Dermatology.
They had already shown that PG has a role in both regulating the function of the major cell type in our skin called keratinocytes and suppressing skin inflammation.
Now they have the first evidence that PG inhibits toll-like receptor activation by the antimicrobial peptides produced by those skin cells, says Dr. Wendy B. Bollag, cell physiologist in the Department of Physiology at the Medical College of Georgia at Augusta University.
Toll-like receptors are a family of receptors that detect external invaders as well as internal damage signals then activate an immune response. Our skin is our largest organ and front line of defense, and a variety of skin cell types make antimicrobial peptides, which function like an endogenous antibiotic to help the skin protect us.
The common skin condition psoriasis upsets the works by increasing both the production of skin cells and production of these antimicrobials by those cells.
In some patients it may be a problematic immune system that initiates the vicious cycle of skin cells producing proteins called cytokines that call in more immune cells that make more cytokines that cause skin cells to make even more cytokines and excessively proliferate, says Bollag. In others, the antimicrobials may initiate the vicious cycle.
Either way, more antimicrobials get produced which is probably beneficial since psoriasis also impairs the skin’s ability to prevent invaders.
But these high levels of antimicrobials also produce an inflammatory response much like an invader’s might, resulting in the red, flaky patches that typically surface on high-touch areas like the elbows, forearms and knees and also show up on the scalp and elsewhere, says Bollag, the study’s corresponding author.
Because at higher levels, the body sees these protective antimicrobial peptides as danger-associated molecular patterns, or DAMPS, which, as the name indicates, it views as signs of danger. DAMPS then activate toll-like receptors.
It’s the increased and chronic level in psoriasis that heightens the awareness and response, says first author Dr. Vivek Choudhary, molecular biologist and physiologist in the MCG Department of Physiology.
Once toll-like receptors get activated, the immune system makes proinflammatory cytokines that bring in T cells, which help drive the immune system attacks.
“It’s actually T cells that help maintain the disease,” Bollag says, “But we are thinking that the innate immune system is sort of what initiates it,” she says of that toll-like receptor activation.
In the continuing vicious cycle, all the immune action prompts the skin cells to actually make more antimicrobials in response to the perceived danger. “It’s a natural system that has kind of gone haywire,” she says.
The investigators used S100A9 as their representative antimicrobial. In psoriasis, the levels of S100A9 correlate with the severity of the disease and, when treatment works, blood levels of S100A9 decrease.
They found that both in keratinocytes as well as inflammation-promoting immune cells called macrophages, PG suppressed activation of toll-like receptors by DAMPS, in this case S100A9.
Next steps include finding a version of PG that can more easily permeate the skin since the larger lipid is a bit too big to easily pass through the natural barrier. Interestingly, psoriasis hinders the barrier function so PG can initially get through, but when the condition improves, PG’s access deteriorates, the investigators note.
They suspect PG’s inhibition of toll-like receptors doesn’t just happen in psoriasis, but that constant fine tuning of the immune response is among its usual functions.
“You want to be able to dial it up, but not go overboard,” Bollag says. “We think that may be part of the job of PG, to basically keep the immune system from going from zero to 60 in one second flat.”
This is particularly important in body areas regularly exposed to the elements like the skin, lungs and gastrointestinal tract, she says. Maybe part of the problem with psoriasis is that this fine control no longer works well, she says.
Inflammation in the absence of an infection is a hallmark of psoriasis. The resulting inflammation produces a “feed forward” response: Keratinocytes start to excessively proliferate and abnormally differentiate and the skin thickens.
PG enables the normal differentiation of new skin cells as cells make their way up multiple layers, reach the surface and old cells slough off.
PG is made from glycerin, a natural alcohol, water attractor and key component of many lipids, which helps skin look better and aids this healthy production and maturation of high-turnover skin cells. Glycerin is transported by aquaporin-3, which the MCG investigators believe is decreased in psoriasis versus healthy skin.
Today there are a variety of topical treatments for psoriasis, including vitamin D analogues and glucocorticoids, but nothing that works great for all patients, Bollag says. Part of the problem likely is that psoriasis causes vary and the reality that they are mostly not understood. Systemic drugs also are given that generally suppress the immune response, which have obvious side effects like leaving patients susceptible to infection and cancer.
Bollag doesn’t think PG will be a magic bullet either, but may one day be a good option for patients with mild disease or as an adjunct to other therapies.
PG is also a component of surfactant, which enables the airs sacs in the lungs to properly inflate so we can breathe. It’s been shown to inhibit inflammation in the lungs induced by microorganisms and that it works there as well through toll-like receptors. Bollag notes these new findings about what happens in the skin are likely applicable to similar conditions, where this so-called “sterile inflammation” occurs in response to substances naturally found in the body.
In a second study, cancer therapy showed promise for psoriasis treatment.
Cancer therapy shows promise for psoriasis treatment
HDAC inhibitors, already widely used to treat cancer, may be an effective therapy for psoriasis as well, scientists report.
They have shown that HDAC3 inhibitors are particularly adept at increasing expression of aquaporin-3, or AQP3, a channel that transports glycerin, a natural alcohol and water attractor, which helps skin look better and aids healthy production and maturation of high-turnover skin cells.
“We’ve found that HDAC3 normally inhibits expression of AQP3 and we think we can use this knowledge to treat patients with psoriasis,” said Dr. Vivek Choudhary, molecular biologist and physiologist in the Department of Physiology at the Medical College of Georgia at Augusta University.
MCG scientists knew that AQP3 levels were lower in psoriasis than in healthy skin, said Choudhary, corresponding author of the study in the Journal of Investigative Dermatology. The protein helps skin cells proliferate, differentiate into the right kind of cells and get to the right location in the body. It also aids the skin’s hydration, wound recovery and elasticity. Histone deacetylase, which they found suppresses AQP3, helps regulate gene expression and protein function.
Since the immune system is believed to play a key role in psoriasis, many current treatments generally suppress the immune response, which increases the risk of infections, even cancer. MCG scientists hope they can one day instead directly enhance the presence of AQP3 or maybe its key cargo glycerin.
Psoriasis is one of the most common skin disorders, with red, flaky patches most often erupting on the elbows, knees, scalp and back, said Dr. Wendy B. Bollag, cell physiologist in the MCG Department of Physiology and the study’s senior author.
Like cancer, inflammation and excessive proliferation of cells are a psoriasis hallmark. That common ground and other emerging clues got the scientists thinking about the treatment potential of HDAC inhibitors. But first they had to establish a relationship.
When they introduced a broad-acting HDAC inhibitor to normal skin cells, or keratinocytes, – both mouse and human – they found expression of AQP3 went up within 24 hours, the first time the relationship had been noted.
They reiterated that AQP3 was critical because when it was missing, there was no commensurate increase in glycerin. AQP3 knockout mice also further clarified AQP3’s role in skin hydration, elasticity and wound healing and that it is glycerin – rather than water – that is most key to these healthy functions.
They also found that p53, a known, natural tumor suppressor that also supports cell differentiation, helps the HDAC inhibitors enable more AQP3 and ultimately more glycerin, Choudhary said. HDACs also are known to inhibit p53 activity. However overexpressing p53 by itself did not result in increased functional levels of AQP3, the scientists found.
The MCG scientists first used the HDAC inhibitor, suberoylanilide hydroxamic acid, or SAHA, which was approved by the Food and Drug Administration more than a decade ago to treat cutaneous T cell lymphoma, which has symptoms that can include dry, itchy skin as well as enlarged lymph nodes.
“We think this is one of the ways it works,” Bollag said of SAHA and their new findings. They also used several other HDAC inhibitors and found the ones that suppressed HDAC3 were also most effective at increasing AQP3.
AQP3 is adept at hauling glycerin, the backbone of many lipids and typically a key ingredient in skin lotion. Bollag’s lab reported in the Journal of Investigative Dermatology in 2003 that glycerin helps skin cells mature properly. Inside skin cells, phospholipase D – an enzyme that converts fats or lipids in the external protective cell membrane into cell signals – and AQP3 interact. AQP3 hands off glycerin, which produces phosphatidylglycerol, which, in turn, aids skin cell differentiation.
“We think phosphatidylglycerol is the key,” Bollag said of the positive results. “If you don’t have enough, you may have psoriasis.”
The Bollag lab and others also had found that AQP3, which is present in psoriasis, appears rather immature and out of place, largely inside the cell cytoplasm instead of on the protective, outer cell membrane. The inner location puts quite a damper on its normal mature function of transporting glycerin, water and other substances through the membrane.
“If you use antibodies to visualize where AQP3 is in the keratinocytes, you will see it nicely outlining the cells because it’s right there on the plasma membrane,” Bollag said. “So clearly it’s normally expressed in keratinocytes but the fact that we can upregulate it even more with an HDAC3 inhibitor suggests that normally HDAC3 keeps it in check.”
Cambridge, Massachusetts-based biotech company Shape Pharmaceuticals Inc., currently has a topical version of an HDAC inhibitor in clinical trials for cutaneous T cell lymphoma. If psoriasis patients end up taking HDAC inhibitors, low doses or a topical application likely would help avoid some side effects, including nausea, Bollag said.
One way HDAC inhibitors help fight cancer is by temporarily loosening DNA, increasing the expression of tumor-suppressing genes and making the tumor more vulnerable. HDAC inhibitors also are being explored for their potential in treating neurological diseases such as Huntington’s.
Others have provided evidence that dysregulation of AQP3 contributes to psoriasis and AQP3 is linked to other skin diseases as well like atopic dermatitis – the most common type of eczema and vitiligo, which results in white patches on the skin.
Interestingly, even though psoriatic cells are known for their propensity to replicate, it’s hard to grow an adequate number of cells for scientific study: they increase a certain amount then go quiet. There also is no real animal model of psoriasis. Moving forward, the MCG scientists may try developing a model using a topical drug for genital warts since some patients who take it develop psoriasis.
Image : Drs. Choudhary and Bollag in the Department of Physiology’s lab at the Medical College of Georgia at Augusta University Credit: Phil Jones, Senior Photographer, Augusta University
Image credit : Phil Jones, Senior Photographer, Augusta University