Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells

• Published in: The Journal of immunology (1950) 2015-07, Vol.195 (2), p.621-631
• Main Authors: Klein, Matthias, Brühl, Till-Julius, Staudt, Valérie, Reuter, Sebastian, Grebe, Nadine, Gerlitzki, Bastian, Hoffmann, Markus, Bohn, Toszka, Ulges, Alexander, Stergiou, Natascha, de Graaf, Jos, Löwer, Martin, Taube, Christian, Becker, Marc, Hain, Tobias, Dietzen, Sarah, Stassen, Michael, Huber, Magdalena, Lohoff, Michael, Campos Chagas, Andrezza, Andersen, John, Kotál, Jan, Langhansová, Helena, Kopecký, Jan, Schild, Hansjörg, Kotsyfakis, Michalis, Schmitt, Edgar, Bopp, Tobias
• Format: Article
• Language: English
• Subjects: Animals; Asthma - genetics; Asthma - immunology; Asthma - pathology; Binding Sites; Cell Degranulation - immunology; Cystatins - immunology; Cystatins - pharmacology; Gene Expression Regulation; Host-Parasite Interactions - immunology; Immunity, Innate - drug effects; Immunosuppressive Agents - pharmacology; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - immunology; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-9 - antagonists & inhibitors; Interleukin-9 - genetics; Interleukin-9 - immunology; Ixodidae; Mast Cells - drug effects; Mast Cells - immunology; Mast Cells - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; Protein Binding; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - immunology; Signal Transduction; Transcription, Genetic
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1401823

Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.