Project 5: Identification and Characterization of Pruritus Pathways in Chronic Skin Inflammation
Project Managers:
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About:
Chronic pruritus has a high prevalence. It severely reduces the quality of life and is difficult to treat. The main problem in the development of targeted therapies has been a lack of pathophysiological concepts and identification of specific itch mediators. Chronic inflammatory skin diseases represent a major cause of chronic pruritus.
In particular, patients with lichen planus, psoriasis and atopic dermatitis experience severe itch. Although these patients commonly suffer from this symptom, the clinical phenotypes, histopathology and underlying inflammatory pathways in these diseases are thought to be fundamentally different. In this project, we will use distinct chronic inflammatory and pruritic skin diseases such as lichen planus (TH1-driven), atopic dermatitis (TH2-driven) and psoriasis (TH17-driven) as models, state of the art biobanking, transcriptomics and in vitro, as well as in vivo models, to address the following aims:
(I) The characterization of known pathways and identification of novel pathways for pruritus associated with chronic skin inflammation;
(II) Validation of the role of known and novel pruritus signaling pathways on neuronal growth in vitro;
(III) Validation of the role of novel pruritus signaling pathways on keratinocytes and the epidermis in vitro;
(IV) The establishment of the specific role of mast cells and eosinophils during IL-31-induced pruritus, skin inflammation and neuronal growth in vivo;
(V) The determination of the role of neuronal Stat3 signaling for the development of IL-31-induced pruritus, skin inflammation and neuronal growth in vitro and in vivo. The findings from this study will increase our understanding of the molecular and cellular pathways that induce pruritus, define and validate biomarkers and identify novel targets for the treatment of chronic pruritus.
In particular, patients with lichen planus, psoriasis and atopic dermatitis experience severe itch. Although these patients commonly suffer from this symptom, the clinical phenotypes, histopathology and underlying inflammatory pathways in these diseases are thought to be fundamentally different. In this project, we will use distinct chronic inflammatory and pruritic skin diseases such as lichen planus (TH1-driven), atopic dermatitis (TH2-driven) and psoriasis (TH17-driven) as models, state of the art biobanking, transcriptomics and in vitro, as well as in vivo models, to address the following aims:
(I) The characterization of known pathways and identification of novel pathways for pruritus associated with chronic skin inflammation;
(II) Validation of the role of known and novel pruritus signaling pathways on neuronal growth in vitro;
(III) Validation of the role of novel pruritus signaling pathways on keratinocytes and the epidermis in vitro;
(IV) The establishment of the specific role of mast cells and eosinophils during IL-31-induced pruritus, skin inflammation and neuronal growth in vivo;
(V) The determination of the role of neuronal Stat3 signaling for the development of IL-31-induced pruritus, skin inflammation and neuronal growth in vitro and in vivo. The findings from this study will increase our understanding of the molecular and cellular pathways that induce pruritus, define and validate biomarkers and identify novel targets for the treatment of chronic pruritus.
Related Publications:
- Pattarini L, Trichot C, Bogiatzi S, Grandclaudon M, Meller S, Keuylian Z, Durand M, Volpe E, Madonna S, Cavani A, Chiricozzi A, Romanelli M, Hori T, Hovnanian A, Homey B, Soumelis V. TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand. J Exp Med 2017; 214(5):1529-46.
- Raap U, Gehring M, Kleiner S, Rudrich U, Eiz-Vesper B, Haas H, Kapp A, Gibbs BF. Human basophils are a source of - and are differentially activated by - IL-31. Clin Exp Allergy 2017; 47(4):499-508.
- Feld M, Garcia R, Buddenkotte J, Katayama S, Lewis K, Muirhead G, Hevezi P, Plesser K, Schrumpf H, Krjutskov K, Sergeeva O, Müller HW, Tsoka S, Kere J, Dillon SR, Steinhoff M, Homey B. The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves. J Allergy Clin Immunol 2016; 138(2):500-8.
- Kunsleben N, Rudrich U, Gehring M, Novak N, Kapp A, Raap U. IL-31 Induces Chemotaxis, Calcium Mobilization, Release of Reactive Oxygen Species, and CCL26 in Eosinophils, Which Are Capable to Release IL-31. J Invest Dermatol 2015; 135(7):1908-11.
- Meller S, Di Domizio J, Voo KS, Friedrich HC, Chamilos G, Ganguly D, Conrad C, Gregorio J, Le Roy D, Roger T, Ladbury JE, Homey B, Watowich S, Modlin RL, Kontoyiannis DP, Liu YJ, Arold ST, Gilliet M. T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol 2015; 16(9):970-9.
- Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, Soumelis V, Feld M, Alenius H, Dillon SR, Carstens E, Homey B*, Basbaum A*, Steinhoff M*. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 2014; 133(2):448-60 (*equal contribution).
- Hartmann K, Wagner N, Rabenhorst A, Pflanz L, Leja S, Forster A, Gehring M, Kapp A, Raap U. Serum IL-31 levels are increased in a subset of patients with mastocytosis and correlate with disease severity in adult patients. J Allergy Clin Immunol 2013; 132(1):232-35.
- Raap U, Weissmantel S, Gehring M, Eisenberg AM, Kapp A, Folster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol 2012; 23(3):285-8.
- Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A, Werfel T. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008; 122(2):421-3.
- Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, Alenius H, Dieu-Nosjean MC, Meller S, Rieker J, Steinhoff M, Hoffmann TK, Ruzicka T, Zlotnik A, Homey B. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006 Feb;117(2):411-7.