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.
- MeSH
- bronchiální astma genetika imunologie patologie MeSH
- cystatiny imunologie farmakologie MeSH
- degranulace buněk imunologie MeSH
- genetická transkripce MeSH
- imunosupresiva farmakologie MeSH
- interakce hostitele a parazita imunologie MeSH
- interferonové regulační faktory nedostatek genetika imunologie MeSH
- interleukin-1beta genetika imunologie MeSH
- interleukin-6 genetika imunologie MeSH
- interleukin-9 antagonisté a inhibitory genetika imunologie MeSH
- mastocyty účinky léků imunologie patologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- přirozená imunita účinky léků MeSH
- promotorové oblasti (genetika) MeSH
- receptory interleukinu-1 genetika imunologie MeSH
- regulace genové exprese MeSH
- signální transdukce MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma.
- MeSH
- bronchiální astma imunologie metabolismus prevence a kontrola MeSH
- cystatiny imunologie farmakologie MeSH
- cytokiny imunologie metabolismus MeSH
- ELISA MeSH
- interleukin-9 biosyntéza imunologie MeSH
- Ixodidae imunologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- myši knockoutované MeSH
- myši MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- průtoková cytometrie MeSH
- separace buněk MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
