RRC ID 36682
Author Puthia M, Ambite I, Cafaro C, Butler D, Huang Y, Lutay N, Rydström G, Gullstrand B, Swaminathan B, Nadeem A, Nilsson B, Svanborg C.
Title IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections.
Journal 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.
Volume 8(336)
Pages 336ra59
Published 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
Times Cited 12
Mice RBRC01420