oa Editorial [ Hot topic:Updates on Therapeutic Approaches to Inflammatory Skin Diseases: From Molecular Targets to Drug Development. Part I (Guest Editors: L. Korkina & S. Pastore) ]

The current Hot Topic Issue, organized in two volumes, is dedicated to the very old health problem of the still incurable chronic skin pathologies, and to novel emerging approaches to pharmacological treatment. Here, we focused mainly on immune-dependent and UV-induced skin disorders with a clear inflammatory component such as psoriasis, atopic and contact dermatitis, UV-induced skin tumors, and photoaging. In the last years, the immune and molecular mechanisms underlying psoriasis, contact dermatitis and atopic dermatitis have been extensively investigated, and relevant steps in their pathogenesis as well as molecular targets for drug development have been identified. The introductory paper by Cristina Albanesi and Saveria Pastore covers these developments and especially highlights the current consensus on the dramatic role of skin keratinocytes in the inflammatory responses of the skin. Far from simply being the bricks for the construction of an effective barrier against environmental insults, keratinocytes are now considered highly active immune cells, with a major control over both the acute and the chronic phases of skin inflammation by means of cytokine/chemokine production and surface adhesion/recognition molecule expression. This introductory chapter puts special emphasis to the fact that recently introduced highly specific, single molecule-targeted biological drugs are offering the best demonstration that an accurate definition of the molecular pathways underlying any pathology is mandatory to identify the relevant therapeutic targets for drug discovery. This is utmost evident from the so-called “biological therapy” of psoriasis presently, but the same approach is under intense evaluation to improve the clinical management of contact and atopic dermatitis. According to this premise, in their review dedicated to contact dermatitis immunotherapy, Andrea Cavani and Anastasia De Luca concentrate on specific molecular pathways-targets for contact dermatitis. In particular, their paper is mainly focused on potentially effective blockers/inhibitors of the adhesion molecules involved in leukocyte-endothelial cell interaction and hence leukocyte extravasation, and against the integrins involved in the immune synapsis precipitating the disease. Finally, the authors express their expert point of view on the potential development of hapten-specific desensitization therapies in contact dermatitis, which aim at boosting and expanding the anti-inflammatory activity of regulatory T cell populations, whose physiological role is evidently compromised in sensitized individuals. Expansion of allergen-specific regulatory T cell populations should represent a valid approach also for atopic dermatitis, a chronic skin disease induced and aggravated by sensitization to environmental protein allergens in a relevant proportion of hyper-responding subjects. The contribution of Claudia Traidl and colleagues offers a complete overview of the pharmacological treatments of atopic dermatitis, which is currently based on local and/or systemic administration of anti-inflammatory drugs. These authors emphasize that, although significant gains have been made during the last years in the understanding of the molecular mechanisms behind this disease, nonetheless its treatment basically aims at symptomatic relief. However, a number of pilot experimental approaches with new drugs, including biologics that neutralize B cells or selectively bind the IgE component of immunoglobulins, is hopefully opening new therapeutic possibilities to patients with severe atopic dermatitis and concomitant sensitization to environmental allergens. The most relevant insult to human skin derives from the UV components of the solar light. It is now well ascertained that both acute and chronic exposure to solar light associates with increased risk of developing a number of pathological states, including chronic inflammation, immunosuppression and carcinogenesis. The UV-initiated molecular processes leading to transient or irreversible damage to the skin are peculiarly manifold and complex, and this fact can be easily perceived by reading the exhaustive review written by Charareh Pourzand and colleague. In particular, she draws our attention to a new molecular aspect, which is the UV-induced release of chelatable iron by cells of human skin, and its intrinsic toxicity for the cell. Iron is a critically important metal for numerous cellular functions. At the same time, abnormal increase of the unbound, labile, and redox active iron can be toxic, essentially due to the iron-catalyzed free radical-driven chain reactions, which are damaging to biologically important molecules and structures. Indeed, presence of excess iron has been recognized in severe human diseases, including neurodegenerative diseases, liver cirrhosis, and cancer, and also in inflammatory skin disorders such as psoriasis and atopic dermatitis. Among the labile iron-induced molecular targets leading to skin damage, there is a persistent NFkappaB activation, which predisposes to inflammation, skin hyperplasia and eventually carcinogenesis. The natural consequence is now the search for a valid pharmacological approach to neutralize labile iron in vivo. Updated and unique description of possible candidates, including synthetic or natural multi-antioxidant substances that should also possess relevant iron-chelating activities, or photo-activated and photo-controlled pro-drugs is provided. Being photo-sensitive, these pro-drugs will exert their activity as iron chelators in situ within the skin only at need, in response to exposure to the sunlight and hence with no perturbation of the physiological labile iron pool....