Elisabetta Volpe1, Lucia Pattarini2, Carolina Martinez-Cingolani2, Stephan Meller3, Marie-Helene Donnadieu4, Sofia I Bogiatzi4, Maria I Fernandez5, Maxime Touzot4, Jean-Christophe Bichet6, Fabien Reyal7, Maria Paola Paronetto8, Andrea Chiricozzi9, Sergio Chimenti10, Francesca Nasorri11, Andrea Cavani11, Andreas Kislat3, Bernhard Homey3, Vassili Soumelis12. 1. Department of Immunology, Institut Curie, Paris, France; Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy. Electronic address: e.volpe@hsantalucia.it. 2. Department of Immunology, Institut Curie, Paris, France; Institut National de la Santé et de la Recherche Médicale U932, Paris, France; Research Section, Institut Curie, Paris, France. 3. Department of Dermatology, Heinrich Heine University, Düsseldorf, Germany. 4. Department of Immunology, Institut Curie, Paris, France; Institut National de la Santé et de la Recherche Médicale U932, Paris, France. 5. Department of Immunology, Institut Curie, Paris, France; Institut National de la Santé et de la Recherche Médicale U932, Paris, France; Department of Microbiology, Infectiology and Immunology, CHU Sainte-Justine and University of Montreal, Montreal, Quebec, Canada; CHU Sainte-Justine Research Center, Montreal, Quebec, Canada. 6. Départment de Chirurgie, Hopital Pitié Salpétrière, Paris, France. 7. Department of Surgery, Institut Curie, Paris, France. 8. Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, Rome, Italy. 9. Department of Dermatology, University of Rome Tor Vergata, Rome, Italy; Laboratory for Investigative Dermatology, Rockefeller University, New York, NY. 10. Department of Dermatology, University of Rome Tor Vergata, Rome, Italy. 11. Laboratory of Experimental Immunology, IDI-IRCCS, Rome, Italy. 12. Department of Immunology, Institut Curie, Paris, France; Institut National de la Santé et de la Recherche Médicale U932, Paris, France; Research Section, Institut Curie, Paris, France. Electronic address: vassili.soumelis@curie.fr.
Abstract
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune inflammation and associated pathways is not known. OBJECTIVE: In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23-associated skin autoimmune disease. METHODS: The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. RESULTS: We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6-independent manner. CONCLUSION: Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune inflammation and associated pathways is not known. OBJECTIVE: In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23-associated skin autoimmune disease. METHODS: The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. RESULTS: We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6-independent manner. CONCLUSION: Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.
Authors: Mårten C G Winge; Bungo Ohyama; Clara N Dey; Lisa M Boxer; Wei Li; Nazanin Ehsani-Chimeh; Allison K Truong; Diane Wu; April W Armstrong; Teruhiko Makino; Matthew Davidson; Daniela Starcevic; Andreas Kislat; Ngon T Nguyen; Takashi Hashimoto; Bernard Homey; Paul A Khavari; Maria Bradley; Elizabeth A Waterman; M Peter Marinkovich Journal: J Clin Invest Date: 2016-06-13 Impact factor: 14.808
Authors: Yu Sawada; Teruaki Nakatsuji; Tatsuya Dokoshi; Nikhil Nitin Kulkarni; Marc C Liggins; George Sen; Richard L Gallo Journal: Sci Immunol Date: 2021-05-21