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Why vitamin D ameliorates psoriasis

Antimicrobial peptide inhibits skin inflammation by a novel mechanism

Munich, 05/13/2011

Silvery scales that itch and flake off, leaving the underlying skin inflamed and exposed, are the hallmarks of psoriasis. In Germany alone, two million people suffer from the condition. It results from a combination of genetic predisposition and environmental factors, which together provoke sensitization of the immune system. A research team led by Dr. Jürgen Schauber at the Medical Center of the University of Munich has now discovered and dissected an entirely new mechanism that contributes to the extreme inflammatory reactions seen in psoriatic skin. He and his group found that extranuclear DNA present in the cytosol of patients’ skin cells activates a protein complex that specifically aggravates the inflammatory response. “However, this mechanism can be inactivated by the binding of an antimicrobial skin protein called cathelicidin LL-37 to the cytosolic DNA,” explains Schauber. Vitamin D is known to promote the production von cathelidicin LL-37 in the skin, so that the inhibitory action of the peptide may possibly account for the therapeutic effects of vitamin D-like agents on psoriasis. The investigators now intend to test whether the new mechanism can be blocked by alternative therapeutic strategies. (Science Translational Medicine, 11 May 2011)

Psoriasis is an irritating and unsightly condition marked by chronic, localized inflammation of the skin and an autoimmune reaction against the keratinocytes, the cells that form the outer protective layer of the skin. Immune activation results in accelerated proliferation of keratinocytes. The skin thickens and the outermost layer flakes off easily. Once the disease becomes manifest, it tends to go through cycles of relapse and recurrence. Stimuli such as skin infections and particular drugs, but also mechanical insults, can trigger the disease. The signal molecule interleukin-1 (IL-1)beta is known to play a key role in its development. IL-1beta is the product of specific cleavage of a precursor protein by so-called inflammasomes, which are molecular complexes that are assembled in cells upon reception of certain danger signals. Schauber describes the aim of the study as follows:  "We were interested in finding out which types of inflammasomes are especially active in psoriatic plaques, how they are activated, and whether they could be inactivated." The team succeeded in demonstrating that the inflammasome AIM2 is particularly active in the skin cells of psoriasis patients. AIM2 reacts specifically to the presence of DNA in the soluble, extranuclear compartment of the cell, known as the cytosol. Binding of cytosolic DNA is interpreted as a danger signal, and AIM2 then activates the synthesis of IL-1beta, which promotes an inflammatory response. "Interestingly, cytoplasmic DNA is indeed present in the skin cells of psoriasis patients. In human cells, DNA is normally found only in the nucleus or encapsulated within the mitochondria, and has no business to be running around free in the cytoplasm," Schauber explains. Further experiments confirmed that the cytosolic DNA was directly responsible for activating AIM2. The origin of the cytosolic DNA is unclear. It may have leaked into the cytosol following damage to the nuclear membrane, or it might represent DNA that was released into the extracellular medium by dying cells, and then taken up by intact cells nearby.

Short proteins found in the skin, so-called antimicrobial peptides (AMPs), are known to act as a defense against bacterial infections. AMPs can also bind DNA. Schauber‘s group has already carried out extensive studies on one of these, called cathelicidin. It is therefore not surprising that the team decided to check whether cathelicidin has any impact on the activation of the AIM2 inflammasome. It turned out that cathelidicin not only binds cytosolic DNA but also neutralizes its pro-inflammatory effect. This observation may explain the therapeutic efficacy of UV light and of preparations containing vitamin D-like compounds in the treatment of psoriasis. Vitamin D stimulates the production of cathelidicin in the skin, and exposure to UVB radiation enhances the synthesis of both vitamin D and cathelidicin. "It is therefore conceivable that the newly discovered action of cathelidicin might provide an alternative target for therapeutic approaches," says Schauber. The next priority for him and his team is to test whether the pro-inflammatory signal initiated by inflammasome activation is also involved in the pathogenesis of other skin conditions associated with chronic inflammation – and whether this process be targeted for therapeutic purposes. (göd/PH)

 

Publication:
Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic Lesions.
Y. Dombrowski, M. Peric, S. Koglin,C. Kammerbauer, C. Göß, D. Anz, M. Simanski, R. Gläser, J. Harder, V. Hornung, R. L. Gallo, T. Ruzicka, R. Besch, J. Schauber
Science Translational Medicine Vol. 3 82ra38, 11 May 2011

 

Contact:
Dr. Jürgen Schauber
Clinic and Outpatient Clinic of Dermatology and Allergology
Phone: +49 (0) 89 5160 6395
Email: juergen.schauber@med.uni-muenchen.de

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