Article | Published:

Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ

Nature Immunology volume 14, pages 461469 (2013) | Download Citation

Abstract

Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation. Genetic disruption of the Miz1 POZ domain, which is essential for the transactivation or repression activity of Miz1, resulted in hyperinflammation, lung injury and greater mortality in LPS-treated mice but a lower bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged the expression of proinflammatory cytokines. After stimulation, Miz1 was phosphorylated at Ser178, which was required for recruitment of the histone deacetylase HDAC1 to repress transcription of the gene encoding C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying the resolution of LPS-induced inflammation.

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Acknowledgements

We thank A. Hauser, K. Gates, A. Gonzalez and F. Aguilar for help with animal experiments; J. Radder for isolating ATII cells; L. He for isolating lung cells derived from the hematopoietic compartment; A. Yemelyanov for lentivirus preparation; and J. Dewille (Ohio State University College of Veterinary Medicine) for the Cebpd luciferase reporter gene construct. Supported by the US National Institutes of Health (GM081603 to J.L., GM095313 to A.L., ES015024 to G.M.M., ES013995 to G.R.S.B., P01HL071643 to J.I.S., and AI 089954 and AI 091962 to L.Z.).

Author information

Author notes

    • Hanh Chi Do-Umehara
    •  & Cong Chen

    These authors contributed equally to this work.

Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Hanh Chi Do-Umehara
    • , Cong Chen
    • , Daniela Urich
    • , Samuel Jang
    • , Alia Zander
    • , Margaret A Baker
    • , Peter H S Sporn
    • , Karen M Ridge
    • , Jacob I Sznajder
    • , G R Scott Budinger
    • , Gökhan M Mutlu
    •  & Jing Liu
  2. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Liang Zhou
    •  & Ju Qiu
  3. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Liang Zhou
    •  & Ju Qiu
  4. Institute of Molecular Biology and Tumour Research, Philipps University Marburg, Universität Marburg, Marburg, Germany.

    • Martin Eilers
  5. Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.

    • Peter H S Sporn
    • , Karen M Ridge
    •  & G R Scott Budinger
  6. Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.

    • Anning Lin
  7. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.

    • Anning Lin

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Contributions

H.C.D.-U. and C.C. did experiments and analyzed the data; D.U., J.Q., S.J. and A.Z. did experiments; M.A.B. isolated ATII cells; M.E., L.Z., P.H.S.S., K.M.R., J.I.S. and A.L. provided reagents; G.R.S.B. and G.M.M. did animal experiments and provided reagents; and J.L. designed and supervised the study, did experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jing Liu.

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DOI

https://doi.org/10.1038/ni.2566

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