Psoriasis is one of the most common chronic inflammatory skin conditions that can also spread to the joints. Triggers of the disease, which usually first appears in adulthood, include stress and UV radiation. However, individuals can also be genetically predisposed to developing psoriasis. It is estimated that between 100 and 125 million people worldwide are affected by the condition; of these, at least a quarter now have some form of psoriatic arthritis which may derive from unappropriately treated forms or additional factors linked to lifestyle or genetic contribution. In a study, a few years ago a research team from MedUni Vienna discovered a key starting point for inhibiting inflammation in both psoriasis and psoriatic arthritis. The researchers’ findings may form the basis for the development of new therapeutic, diagnostic and prevention strategies. The study, conducted by the research team led by Erwin Wagner from the Department of Dermatology and Department of Laboratory Medicine, focused on the protein S100A9.
Activation of S100A9 in skin and immune cells has previously been identified as a risk factor for the development of psoriasis and/or RAPS. Similarly, S100A7 (psoriasis), S100A8 (calgranulin C), S100A9, and A12 are protein complexes produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. In skin, the antimicrobial proteins psoriasin and koebnerisin (S100A15) are overexpressed in the epidermis of psoriatic lesions and mediate inflammation by attracting immune cells. Multiple S100 proteins bind TLR4 and RAGE. The ectodomain of RAGE is composed of three immunoglobulin domains, and several S100 proteins can bind each domain. Since multiple S100 proteins are typically associated with specific pathologies (e.g., S100A8/S100A9, S100A4 and S100B elevated in the serum of patients with ARE), this raises the question of whether distinct S100 proteins may elicit differential signaling responses via interactions with the same surface receptors.
Recent studies with S100A8/S100A9 suggest that oligomerization may locally limit S100 activity. Biochemical and cellular studies indicate that extracellular S100A8/S1009 elicits many of its effects via interactions with TLR4 and RAGE receptors. While the S100A8/S100A9 heterodimer can bind TLR4, the higher calcium ion concentrations found in the extracellular environment (in the range of 2–3 mM such as in the skin itself) induce the formation of S100A8/S100A9 tetramers. This masks the TLR4 binding interface on the S100A8/S100A9 dimer, providing a mechanism to modulate the biological activity of the S100 proteins themselves. In contrast, S100A8 or S100A9 homodimers, which also bind TLR4, do not form tetramers. As their previous research has shown, psoriasis symptoms disappear when the S100A9 gene is turned off in all cells of the body. Keratinocytes express S100A8/A9 in response to stress, including wound healing and exposure to detergents.
The latter, in fact, stimulate the CD1 receptor signaling found in the skin layer and in local immune cells. Another important finding is that the levels of S100A8, S100A9 and S100A15 are effectively reduced in the white blood cells of patients who undergo UVB skin irradiation. This confirms the popular custom of patients to expose themselves to sunlight in summer and winter to control the disease, beyond the intake of drugs. UVB is thought to exert immunosuppression in psoriasis in part by inhibiting Th17 and interferon signaling pathways in the skin. It is not entirely clear whether UVB therapy has an effect on systemic inflammation in psoriasis. Some studies have shown reduced levels of IL-17A, TNF-α, S100A15, S100A7, S100A9 and IL-6 gene expression in white blood cells after UVB treatment in psoriasis patients, while other pro-inflammatory mediators such as sVCAM-1, sICAM-1, soluble E-selectin, MMP-9 and MPO did not show significant reductions.
In the human RAPS samples studied by the team, synovial S100A9 levels were higher than the respective serum levels. Importantly, RAPS patients had significantly higher serum concentrations of S100A9, calprotectin, VEGF, IL-6 and TNFα compared to psoriasis-only patients, but only S100A9 and calprotectin could effectively discriminate healthy individuals, psoriasis patients and RAPS patients. Preclinical experiments have been able to shed light on the particular influence that the skin and immune cells in which S100A9 is produced have on the severity of the disease. Therefore, any drugs that inhibit S100A9 will have to be administered systemically, orally or intravenously. Indeed, there is the possibility of interfering with the S100 proteins in an indirect or direct manner. For example, the transcription of S100A4 is directly mediated by the β-catenin/TCF complex and compounds that induce its degradation or block its formation (e.g. niclosamide and sulindac) inhibit the transcription of S100A4.
Instead duloxetine, an SNRI antidepressant, has recently been identified as an inhibitor of S100B transcription. Several anti-allergy drugs such as cromolyn, tranilast, and olopatadine have been reported to bind multiple S100 proteins. The old anti-asthmatic and anti-allergy drug Amlexanox, among its targets, is an antagonist of S100A13 that blocks its interaction with the growth factor FGF1, and inhibits the release of the S100A13-FGF1 complex in vivo. Phenothiazines such as promethazine (in the old Fargan ointment) and other neuroleptics can also interact directly with some S100 proteins, especially A4. There are also compounds such as the inhibitors paquinimod and tasquinimod that disrupt the interaction of S100A8/S100A9 with TLR4 and RAGE. Although these compounds have been evaluated for their ability to disrupt specific target-S100 interactions, it is not known whether they can inhibit the binding of all ligands for a particular S100 protein.
Although current efforts are focused on improving the affinity, selectivity, and biological half-life of these S100 inhibitors, a number of these compounds have been evaluated in mouse models of disease and some have moved into human clinical trials. Paquinimod reduces inflammation and disease progression and/or severity in several inflammatory models, but there are currently no clinical trials of these molecules in the context of psoriasis. Significant progress has been made in understanding the intracellular and extracellular functions of S100 proteins and their roles in modulating inflammatory and other responses that contribute to the development and progression of cancers and chronic, autoimmune, and inflammatory diseases. Despite this progress, a detailed understanding of the cell surface receptors that mediate extracellular S100 signaling is lacking. Finally, scientists know that although the S100 protein family is homogeneous, their molecular geometry is not at all superimposable among their members.
This complicates the possibility of applying a drug that is active on an S100A with another that may not have the molecular pocket for that drug. The good thing is that they all seem to prefer molecules soluble in fat and almost all of the drugs listed above have this characteristic. So it is only a matter of time before molecules specific to the S100 proteins involved in psoriasis are identified. Alternatively, pharmacological repositioning is a strategy that has worked so far: searching among existing drugs, one or two of them that can interact with the S100A9 protein, could be easier and faster than designing a molecule starting from a lot of raw data.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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