store-operated calcium influx; TH17 lymphocytes; keratinocytes; insulin resistance; psoriasis
Brembilla Nicolo Costantino, Senra Luisa, Boehncke Wolf-Henning (2018), The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond, in Frontiers in Immunology
, 9, 1682-1688.
Girolomoni G., Strohal R., Puig L., Bachelez H., Barker J., Boehncke W.H., Prinz J.C. (2017), The role of IL-23 and the IL-23/T H 17 immune axis in the pathogenesis and treatment of psoriasis, in Journal of the European Academy of Dermatology and Venereology
Brembilla N.C., Stalder R., Senra L., Boehncke W.-H. (2017), IL-17A localizes in the exocytic compartment of mast cells in psoriatic skin, in British Journal of Dermatology
Boehncke Wolf-Henning, Brembilla Nicolo Costantino (2017), Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment, in Clinical Reviews in Allergy & Immunology
Buerger Claudia, Shirsath Nitesh, Lang Victoria, Berard Alina, Diehl Sandra, Kaufmann Roland, Boehncke Wolf-Henning, Wolf Peter (2017), Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation, in PLOS ONE
, 12(7), e0180853-e0180853.
Fernandez Marylise, Sutterlüty-Fall Hedwig, Schwärzler Christoph, Lemeille Sylvain, Boehncke Wolf-Henning, Merat Rastine (2017), Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition, in Cancer Medicine
, 6(7), 1652-1664.
Brembilla Nicolò Costantino, Boehncke Wolf-Henning (2017), Dermal adipocytes’ claim for fame in psoriasis, in Experimental Dermatology
, 26(5), 392-393.
Senra Luisa, Stalder Romaine, Alvarez Martinez David, Chizzolini Carlo, Boehncke Wolf-Henning, Brembilla Nicolò Costantino (2016), Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis, in Journal of Investigative Dermatology
, 136(10), 1970-1980.
Boehncke W (2016), Psoriasis and Psoriatic Arthritis: Flip Sides of the Coin?, in Acta Dermato Venereologica
, 96(4), 436-441.
Boehncke Wolf-Henning, Schön Michael P (2015), Psoriasis, in The Lancet
, 386(9997), 983-994.
Psoriasis is a common skin disease, characterized by cutaneous inflammation and hyperproliferation as well as altered differentiation of keratinocytes. Understanding psoriasis pathogenesis advances through integration of key findings in different fields of research. It is now clear that an intense cross-talk takes place between cells of the adaptive as well as the innate immune system, affecting also the functional state of resident cells of the skin, namely endothelial cells and keratinocytes, which in turn feed back to immune cells. Furthermore, there is consensus regarding the central role of TH17 cells. Inflammation-induced insulin resistance attracts more and more attention as a mechanism explaining both endothelial dysfunction (and thus cardiovascular comorbidities) as well as “epithelial dysfunction” (and thus much of psoriasis’ epidermal phenotype). Finally, store-operated calcium entry is now known to be important for both T-cell and keratinocyte function. The proposed project intends to help integrating these novel findings by analysing in detail the interplay of TH17 cells and keratinocytes through all IL-17 isoforms with emphasis on Orai1-mediated store-operated calcium entry and insulin resistance. The specific aims are as follows:•Ex vivo mapping of cells producing IL-17 isoforms, expressing IL-17 receptors, and Orai1 expression in healthy and diseased human skin •In vitro analyses of effects mediated by IL-17 isoforms on the functional state of keratinocytes•In vitro characterization of the main signaling pathways and molecules involved in IL-17 mediated effects in T-cells and keratinocytes •In vitro analysis of Orai1 expression and function in skin- and blood-derived TH17•In vitro analyses on the impact of Orai1-mediated calcium influx on insulin receptor signalling in keratinocytes•In vivo analyses on therapeutic effects of inhibiting store-operated calcium influx in mouse models of cutaneous inflammation/psoriasis The results are of direct clinical importance, as TH17 cells, IL-17, Orai1 and kinases involved in insulin receptor signaling are all valid targets for innovative therapeutic strategies in inflammatory disorders in general and psoriasis in particular.