| 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
|
| リソース情報 |
| 実験動物マウス |
RBRC01420 |
