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A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses

Abstract

Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses1 and their transcription is regulated by a variety of transcription factors2; principal among these is the family of interferon regulatory factors (IRFs)3. The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3–IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.

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Figure 1: FOXO3 is a negative regulator of the antiviral response.
Figure 2: FOXO3 keeps the Irf7 gene in check.
Figure 3: IFN-β represses FOXO3.
Figure 4: Antiviral responses lead to increased lung injury in the absence of FOXO3 and IRF7.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray and ChIP–Seq raw data have been submitted to the Gene Expression Omnibus under accession number GSE37052.

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Acknowledgements

We thank K. A. Kennedy and J. J. Peschon for discussions and critical reading of the manuscript; and S. A. Danziger, T. Stolyar and E. van Gaver for technical assistance. This work was supported by grants and contracts from the National Institutes of Health (R01AI025032, R01AI032972, HHSN272200700038C, HHSN272200800058C and U54GM103511).

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V.L. designed experiments, carried out all experimental studies and drafted the manuscript; A.V.R. performed data mining and microarray data analysis; A.E.L. provided technical assistance for experiments, including quantitative real-time PCR, ChIP and in vivo studies; F.S. carried out western blots; A.C.H. and A.R. performed ChIP-Seq data analysis; A.G.R. did genome-wide motif scanning analysis; A.B. did in vivo studies; J.D.A. supervised the computational analysis and A.A. supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Alan Aderem.

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The authors declare no competing financial interests.

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Litvak, V., Ratushny, A., Lampano, A. et al. A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421–425 (2012). https://doi.org/10.1038/nature11428

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