論文 - 詳細
| RRC ID | 36682 |
|---|---|
| 著者 | Puthia M, Ambite I, Cafaro C, Butler D, Huang Y, Lutay N, Rydström G, Gullstrand B, Swaminathan B, Nadeem A, Nilsson B, Svanborg C. |
| タイトル | IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections. |
| ジャーナル | Sci Transl Med |
| Abstract |
Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF-7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3(-/-) mice with kidney pathology, which was absent in Irf7(-/-) mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3(-/-) mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection. |
| 巻・号 | 8(336) |
| ページ | 336ra59 |
| 公開日 | 2016-4-27 |
| DOI | 10.1126/scitranslmed.aaf1156 |
| PII | 8/336/336ra59 |
| PMID | 27122612 |
| MeSH | Animals Bacterial Infections / immunology* Bacterial Infections / metabolism Female Gene Expression Regulation / genetics Gene Expression Regulation / physiology Humans Immunity, Innate / genetics Immunity, Innate / physiology* Interferon Regulatory Factor-3 / genetics Interferon Regulatory Factor-3 / metabolism Interferon Regulatory Factor-7 / genetics Interferon Regulatory Factor-7 / metabolism* Kidney / metabolism Mice Mice, Inbred C57BL Pyelonephritis / genetics Pyelonephritis / metabolism Signal Transduction / genetics Signal Transduction / physiology |
| IF | 16.304 |
| 引用数 | 12 |
| WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 18 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC01420 |