title: Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells.
abstract: 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.
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Till-Julius
authors.initials: TJ
authors.lastname: Brühl
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Valérie
authors.initials: V
authors.lastname: Staudt
authors.affiliation: III. Medical Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Nadine
authors.initials: N
authors.lastname: Grebe
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Bastian
authors.initials: B
authors.lastname: Gerlitzki
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Toszka
authors.initials: T
authors.lastname: Bohn
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Ulges
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Natascha
authors.initials: N
authors.lastname: Stergiou
authors.affiliation: Translational Oncology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;
authors.forename: Jos
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: Translational Oncology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Löwer
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands;
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Marc
authors.initials: M
authors.lastname: Becker
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Hain
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Dietzen
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.affiliation: Institut für Medizinische Mikrobiologie und Krankenhaushygiene, 35043 Marburg, Germany;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Huber
authors.affiliation: Institut für Medizinische Mikrobiologie und Krankenhaushygiene, 35043 Marburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Lohoff
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Andrezza
authors.initials: A
authors.lastname: Campos Chagas
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: John
authors.initials: J
authors.lastname: Andersen
authors.affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, 37005 České Budějovice, Czech Republic; and.
authors.forename: Jan
authors.initials: J
authors.lastname: Kotál
authors.affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, 37005 České Budějovice, Czech Republic; and Faculty of Science, University of South Bohemia, 37005 České Budějovice, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Langhansová
authors.affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, 37005 České Budějovice, Czech Republic; and Faculty of Science, University of South Bohemia, 37005 České Budějovice, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecký
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, 37005 České Budějovice, Czech Republic; and.
authors.forename: Michalis
authors.initials: M
authors.lastname: Kotsyfakis
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany; boppt@uni-mainz.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001665:Binding Sites; D015550:Cell Degranulation / Q000276:immunology; D015891:Cystatins / Q000276:immunology / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006790:Host-Parasite Interactions / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016906:Interleukin-9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
chemical_list: D015891:Cystatins; D007166:Immunosuppressive Agents; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; D015850:Interleukin-6; D016906:Interleukin-9; D017472:Receptors, Interleukin-1; D000099218:Interferon Regulatory Factor-4; C515505:sialostatin L, Ixodes scapularis